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A. Rimner



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    MO17 - Radiotherapy I: Stereotactic Ablative Body Radiotherapy (ID 106)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Radiation Oncology + Radiotherapy
    • Presentations: 1
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      MO17.09 - Dosimetric Predictors of Esophageal Toxicity after Stereotactic Body Radiotherapy for Central Lung Tumors (ID 1674)

      17:05 - 17:10  |  Author(s): A. Rimner

      • Abstract
      • Presentation
      • Slides

      Background
      Stereotactic body radiotherapy (SBRT) is an effective treatment for early-stage non-small cell lung cancer (NSCLC) and lung metastases. However, increased toxicity has been observed for SBRT to lesions near the proximal airways or mediastinal structures. Reported toxicities have primarily pertained to pulmonary complications, but little is known about the risk for esophageal toxicity. Therefore, we sought to evaluate dosimetric predictors of esophageal toxicity in this patient cohort at our institution.

      Methods
      We identified 125 patients who received SBRT for single lung tumors within 2 cm of the proximal bronchial tree (n=81) or whose planning target volume (PTV) intersected mediastinal structures (n=44). Ninety-one patients had primary NSCLC, 12 had recurrent NSCLC, and 22 had metastatic tumors involving the lung. Patients with prior thoracic radiotherapy were excluded. Toxicity was scored using the Common Terminology Criteria for Adverse Events v.4.0. Biological equivalent doses (BED) were calculated using the linear quadratic formula with either α/β=3 or 10 Gy. Dose-volume histogram variables for the esophagus (D~v~, minimum dose to the hottest volume v and V~d~, volume receiving doses greater than d) were then examined for all patients and correlation with toxicity was assessed using logistic regression. Log rank tests were performed using median splits for variables that were significant in logistic regression.

      Results
      With a median follow-up of 14.3 months, the overall rate of grade ≥2 esophageal toxicity was 12.8% (n=16), including two grade 3 events. The median prescription dose was 45Gy. The most common fractionation schemes were 45Gy in 5 fractions (n=56), 48Gy in 4 fractions (n=21), or 50Gy in 5 fractions (n=14). Highly significant logistic models were generated on the basis of D~3.5cc~, D~5cc~, and D~max ~(p<0.001). For a complication rate < 20%, D~3.5cc~ ≤ 29.4 Gy~10~, D~5cc~ ≤ 25.4 Gy~10~, and D~max~ ≤ 50.1 Gy~10~ was observed based on these models (BED~10~). Log rank tests showed that at 2 years, the probability of complication of those with a BED~10~ D~3.5cc~ > 16.6 Gy was 25% (p<0.001), D~5cc~ > 15.1 Gy was 26% (p<0.001), and a D~max~ > 29.6 Gy was 21% (p=0.032). The probability of complication for those with a D~3.5cc~, D~5cc~, and D~max~ (BED~10~) less than or equal to the above limits were 2%, 2% and 7%, respectively. The analysis was insensitive to α/β, and the same D~v~ variables were found to be significant using α/β =3.

      Conclusion
      This is a novel quantitative analysis providing dose guidelines for significant esophagitis in the setting of SBRT. Dose to the hottest 3.5cc, 5cc and D~max~ were the best parameters for prediction of esophageal toxicity. Converting the BED~10~ limits to physical doses, D~3.5cc ~to the esophagus should be kept less than 18.3, 19.7 and 20.8 Gy for 3, 4, and 5 fractions, respectively, to keep the esophagitis rate < 20%. However, these guidelines must be weighed against clinical considerations and potential compromise of target coverage. This information will be valuable for treatment planning and identifying patients at risk for esophageal complications from SBRT.

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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)

      10:50 - 11:00  |  Author(s): A. Rimner

      • 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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    P1.08 - Poster Session 1 - Radiotherapy (ID 195)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Radiation Oncology + Radiotherapy
    • Presentations: 1
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      P1.08-017 - Factors Influencing Utilization of Prophylactic Cranial Irradiation in Limited-Stage Small Cell Lung Cancer (ID 1915)

      09:30 - 09:30  |  Author(s): A. Rimner

      • Abstract

      Background
      Prophylactic cranial irradiation (PCI) improves survival in limited-stage small cell lung cancer (LS-SCLC). However, PCI is not always delivered to these patients, possibly due to concerns about neurocognitive effects. Efforts to reduce neurotoxicity of PCI, such as hippocampal-sparing radiation, may mitigate these concerns. Little is known about the utilization rate of PCI and the reasons it is not delivered. Therefore, we reviewed the experience with LS-SCLC at a large academic institution to determine the rate of PCI use and factors associated with the lack of use.

      Methods
      We retrospectively reviewed all patients with LS-SCLC treated at our institution between 2000 and 2012. Receipt of PCI was recorded, as well as information about clinical presentation and initial treatment. In patients who did not receive PCI, we reviewed clinical notes from both medical and radiation oncologists to determine the reason. Overall survival (OS) and brain metastasis-free survival (BMFS) were estimated using the Kaplan-Meier technique. Pearson’s chi-squared test was used to evaluate factors associated with PCI use.

      Results
      We identified 229 patients treated with thoracic radiotherapy (TRT) for LS-SCLC at our institution. Median followup was 15.1 months. Of these, 119 (52.0%) did not receive PCI. Thirty-three patients (27.7%) had progressive disease or concern for progression after initial therapy and therefore did not receive PCI. The next most common causes for no PCI were patient refusal (n=25, 21%) or deemed medically unfit by an oncologist (n=25, 21%). In 20 patients (16.8%), the reason for lack of PCI could not be ascertained. Other infrequent causes were patient death or lack of followup (n=8), age (n=3), and prior radiotherapy to the head (n=2). Patients who did not get PCI were significantly older (p<0.001) and had worse performance status at initial presentation (p<0.001). Patients who received sequential rather than concurrent chemoradiation, or who received once-daily rather than twice-daily TRT, were also significantly less likely to receive PCI (p<0.001). Patients who did not receive PCI had significantly worse OS (median 17 vs. 30 months, p=0.01) and BMFS (71% vs. 91% at 1 year, p=0.02) than those who did.

      Conclusion
      Even at a major academic center, fewer than half of patients with LS-SCLC ultimately receive PCI. Patients receiving PCI had better intracranial control. They also had better OS, but this is likely also attributable to other clinical and treatment characteristics. Younger and fitter patients, as well as those receiving optimal TRT, are significantly more likely to undergo PCI. The most common reason for lack of PCI is progression of disease after initial therapy, which is clinically appropriate. However, a significant number of patients are appropriate for PCI yet refuse therapy, generally due to concerns about toxicity. PCI is withheld from an equivalent number of patients due to oncologist concerns about ability to tolerate therapy. This indicates that efforts to reduce neurotoxicity of PCI, such as hippocampal-sparing radiation, may impact a significant number of patients with LS-SCLC and expand the application of this survival-enhancing intervention.

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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 - 09:30  |  Author(s): A. Rimner

      • 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.

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    P3.08 - Poster Session 3 - Radiotherapy (ID 199)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Radiation Oncology + Radiotherapy
    • Presentations: 1
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      P3.08-013 - High local control rates with post-operative radiation therapy in incompletely resected non-small cell lung cancer (NSCLC) patients (ID 1659)

      09:30 - 09:30  |  Author(s): A. Rimner

      • Abstract

      Background
      Post-operative radiation therapy (PORT) is frequently given to patients with NSCLC who have microscopically positive margins (R1 resection) or gross residual disease (R2 resection) based on oncologic first principles. However, the data to support this practice is scarce. Here we report our institutional experience comparing patients who received PORT in the setting of R0, R1 or R2 resections.

      Methods
      Between 1999 and 2012, 203 patients with NSCLC were treated with PORT in 25-39 fractions to 45-70 Gy. All surgery and PORT were performed at our institution. Twenty-one patients had a sublobar resection, 158 had a lobectomy, and 24 underwent a pneumonectomy. PORT was given to R0 patients with pathologic N2 disease, R1 or R2 resections. Patients with negative margins were compared to patients with residual disease (R1 and R2 resections). Patients with tumor recurrence within the PORT field were recorded as local failures. Local failure-free survival (LFFS), disease-free survival (DFS) and overall survival (OS) were calculated using the Kaplan-Meier method. Univariate analysis was performed using the log-rank test.

      Results
      Fifty-five of 203 patients had residual disease after resection; 45 had R1 and 10 had R2 resections. The predominant histology was adenocarcinoma (80%). Stage at diagnosis was stage I-II in 17 patients, stage III in 186 patients. One-hundred and twenty-six (62%) patients received neoadjuvant and 39 (19%) adjuvant chemotherapy. Median age was 60 years and median KPS before PORT was 80. Median interval from surgery or adjuvant chemotherapy to PORT initiation was 1.6 months (range of 0-3.7 months). With a median follow up of 21 months, local failure occurred in 33/148 (22%) without and 14/55 (25%) patients with residual disease. Two- and 5-year actuarial LFFS rate were 79%/66% for R0 and 75%/58% for R1/R2 resections. Two- and 5-year actuarial DFS rate were 44%/30% for R0 and 48/26% for R1/R2 resections. Two-year and 5-year overall survival (OS) for all patients were 62.4% and 33.1%. LFFS, DFS and OS were not significantly different when comparing R0 to R1/R2 resections. Radiation dose, KPS, T-stage, N-stage, lymphovascular invasion, histology and chemotherapy were all not found to be significantly associated with any endpoint. OS was significantly worse for patients with R2 resection compared to R0/R1 resection (2-year OS 20% vs 64%; p= 0.002) and patients with age >65 (p=0.03). Multivariate analysis will be presented.

      Conclusion
      PORT results in equivalent local control rates after R1 and R2 resections when compared to R0 resections. This suggests that PORT has a significant role in local control of residual disease. However, OS was significantly worse for patients with gross residual disease postoperatively.