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Y. Yamada



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    O14 - Radiotherapy - Toxicity and Clinical Trials (ID 105)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Radiation Oncology + Radiotherapy
    • Presentations: 1
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      O14.03 - Using generalized equivalent uniform dose (gEUD) to model volume effects for brachial plexopathy after high-dose stereotactic body radiation therapy (SBRT) (ID 2835)

      10:30 - 12:00  |  Author(s): Y. Yamada

      • Abstract
      • Presentation
      • Slides

      Background
      Brachial plexopathy is a rare but important toxicity of radiation therapy because of its significant impact on quality of life. For standard fractionated raiation therapy, good models of brachial plexus (BP) tolerance exist. However, the tolerance of the BP to SBRT is not well understood. We combined data from SBRT for apical lung and metastatic lesions near the BP spanning a wide range of doses and hypofractionation schemes. We determined the clinical incidence of brachial plexopathy and modeled the correlation with generalized equivalent uniform dose (gEUD) for both physical and biologically effective doses (BED) using a range of fractionation-sensitivity parameters (α/β) and volume effect parameters (a).

      Methods
      Between 2004 and 2012, 180 lesions (76 lung lesions and 104 metastatic lesions) located above the aortic arch and below the level of C3 were treated with SBRT. Patients with prior radiation therapy to this region were excluded. Metastases were treated to 14-30 Gy in 1-5 fractions and lung tumors to 22-60 Gy in 1-5 fractions. The BP was contoured per RTOG atlas definitions. For 54 centrally located spine metastases, both left and right BP were contoured and analyzed separately for a total of 234 BPs in 180 patients. Brachial plexopathy of ≥grade 1 (CTCAE v4.0) was the primary endpoint. Maximum dose to the BP (Dmax), minimum dose to the hottest 5% of the BP (D05), and their respective BEDs were calculated using α/β= 3 Gy. The gEUD was also calculated with the volume effect parameter (a) ranging from log~10~a= -1.0 to +1.0 in log~10~a steps of 0.1. A logistic regression model (LR) was fit to the data as a function of a. Clinical dose recommendations were derived with logrank tests using median splits.

      Results
      With median follow-up of 15.1 months, brachial plexopathy due to SBRT occurred in 9/234 BPs. Severity of brachial plexopathy was grade 1 in two, grade 2 in five and grade 3 in two patients. Median time to onset of brachial plexopathy was 6.2 months and the 1-/2-year actuarial rates were 3.3%/5.6%. For all patients the median BED for BP Dmax was 117.5 Gy and for D05 was 89.3 Gy. Median BED Dmax for patients with and without brachial plexopathy was 234 Gy and 115.2 Gy respectively (p=0.002). Brachial plexopathy was significantly associated with BP BED Dmax (p=0.002), and D05 (p=0.015), but not with physical dose. Using LR, the strongest correlation of gEUD with brachial plexopathy occurred for log~10~a= 1.0 using BED (p=0.002), which is representative of the BED Dmax. LR models of BED Dmax versus brachial plexopathy for various α/β values showed that any α/β<25 was a significantly better predictor than physical dose.

      Conclusion
      Brachial plexopathy is significantly associated with BED Dmax ≥117.5 Gy (equivalent to a physical dose of 17 Gy x1, 9.3 Gy x3 or 7 Gy x5 fractions) and D05 ≥89.3 Gy. BED Dmax was the most important predictor of this rare but serious toxicity.

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    P2.11 - Poster Session 2 - NSCLC Novel Therapies (ID 209)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P2.11-025 - Erlotinib versus Radiation Therapy for Brain Metastases in Patients with EGFR-Mutant Lung Adenocarcinoma (ID 1904)

      09:30 - 16:30  |  Author(s): Y. Yamada

      • Abstract

      Background
      Radiation therapy (RT) is a principal modality in the treatment of patients with brain metastases (BM). However, given the activity of EGFR tyrosine kinase inhibitors (EGFR-TKIs) in the central nervous system, it is uncertain whether upfront brain RT is necessary for EGFR mutated lung adenocarcinoma patients with BM treated with EGFR-TKIs.

      Methods
      We identified all patients treated from 2006-2012 with EGFR-mutated NSCLC with BM at our institution. We evaluated the clinical outcomes of these patients who developed brain metastases and received EGFR-TKI and/or CNS radiotherapy. Endpoints included intracranial progression (ICP), extracranial progression (ECP) and overall survival (OS). All endpoints were measured from development of BM.

      Results
      222 patients were identified. Patients were excluded if they were on an EGFR-TKI prior to the development of BM (n=57), if they possessed a de novo EGFR-TKI resistance mutation (n=6), or if there was incomplete data (n=48). Of the remaining 111 patients, 64 were treated initially with erlotinib, 32 with whole brain RT (WBRT), and 15 with partial brain radiation (PBI). Median follow-up was 20 months (mos). Median age was 61 years (range 26-89). Patients were predominantly female (68%), stage IV at diagnosis (92%), never-smokers (61%), RPA class II (87%), and neurologically asymptomatic (82%). Patients had a median of 4 BM (range 1-30) with a median largest diameter of 10mm. In the erlotinib group, erlotinib was given as monotherapy in 91% and combined with chemotherapy in 9% of patients. 38% of these patients (n=24) eventually received WBRT or PBI a median of 17 mos after diagnosis of BM (range 5-40 mos). Median OS for the whole cohort was 29 mos with a 2-yr OS of 59%. There was no significant difference in OS between the WBRT (median 35 mos) and erlotinib (median 26 mos) groups (p=0.59 by Cox model) though patients treated with PBI had a longer OS (median 64 mos). On univariate analysis, KPS (p<.001), RPA class (p<.001) and PBI (vs. erlotinib, p=.005) were significant, with only RPA class (p=.007) and KPS (p<.001) remaining significant on multivariate analysis. Median time to intracranial progression (ICP) was 17 months for the entire cohort. There was a longer time to ICP in patients who received WBRT (median 24 mos) vs. erlotinib upfront (median 16 mos, p<.05), though this effect was no longer significant on multivariate analysis. Patients in the erlotinib or PBI group were more likely to fail intra-cranially as a component of first failure (58% and 71%, respectively), while upfront WBRT patients were more likely to fail extracranially first (76%).

      Conclusion
      The survival of EGFR-TKI naïve patients with EGFR-mutated NSCLC with BM is notably long, whether they receive upfront erlotinib or brain RT. We observed longer intracranial control with WBRT, but this effect is potentially due to other confounding variables. Though retrospective, this analysis suggests that deferring brain RT in favor of EGFR-TKI is a reasonable strategy for patients with EGFR-mutated NSCLC with BM.