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A. Rimner
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ED15 - Thymic Malignancies: Update on Treatment (ID 285)
- Event: WCLC 2016
- Type: Education Session
- Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
- Presentations: 1
- Moderators:H. Wakelee, P.E. Van Schil
- Coordinates: 12/07/2016, 14:30 - 15:50, Hall C1
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ED15.04 - Radiation of Thymic Malignancies (ID 6510)
15:10 - 15:25 | Author(s): A. Rimner
- Abstract
- Presentation
Abstract:
Radiation therapy (RT) plays an important role in the multimodality management of thymic malignancies. It can be employed in the neoadjuvant, adjuvant, definitive or palliative setting. Adjuvant RT is the most extensively studied setting for RT in thymic malignancies. After complete resection there is likely no role for adjuvant RT for patients with stage I thymomas, a possible role for patients with stage II thymomas, and likely a survival benefit in patients with stage III and IV thymomas. Several recent large database and population-based studies have detected a survival benefit for advanced thymomas, while the results for stage II thymomas have been mixed. For thymic carcinomas the impact of adjuvant RT appears more significant. Several large database and population-based studies have consistently reported a survival benefit with adjuvant RT for thymic carcinoma across various disease stages. For incompletely resected thymic tumors there is a stronger rationale for adjuvant RT based on emerging data and general oncologic principles. Neoadjuvant RT has been mostly explored in thymic carcinoma and demonstrated high response and operability rates. Definitive RT is an excellent treatment option for patients with unresectable thymic malignancies. While most thymic tumors are resectable, a subset of patients is technically or medically inoperable, due to invasion of critical structures or comorbidities. In general, thymic malignancies are radiosensitive, allowing for long-term local control rates. Palliative RT should be considered even in the recurrent or metastatic setting. Image-guided hypofractioned ablative RT may be used for oligometastatic disease as an alternative to surgical resection and has been shown to be a highly effective treatment modality with >90% long-term local control rates and minimal morbidity. Conventional palliative RT is an important modality to improve quality of life by alleviating pain, treating SVC syndrome, airway compression and other symptoms. Modern radiation therapy techniques such as 3D conformal radiation therapy or intensity-modulated radiation therapy should be used to minimize morbidity from treatment. Proton therapy may have advantages in certain clinical scenarios and is currently under investigation.
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MA13 - Modern Technologies and Biological Factors in Radiotherapy (ID 395)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Radiotherapy
- Presentations: 1
- Moderators:M. Thomas, P. Mitchell
- Coordinates: 12/06/2016, 16:00 - 17:30, Stolz 1
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MA13.07 - Tumor-Targeted Radiation Promotes Abscopal Efficacy of Regionally Administered CAR T Cells: A Rationale for Clinical Trial (ID 5456)
17:24 - 17:30 | Author(s): A. Rimner
- Abstract
- Presentation
Background:
Our laboratory has demonstrated the augmented anti-tumor efficacy of intrapleurally administered cancer-antigen mesothelin (MSLN)-targeted chimeric antigen receptor (CAR) T cells (Sci Transl Med 2014), and translated the approach to a clinical trial (NCT02414269) for thoracic malignancies. We hypothesized that regionally administered MSLN CAR T cells can circulate systemically to achieve abscopal anti-tumor efficacy in an antigen-specific manner, and the abscopal efficacy can further be promoted by tumor-targeted radiation therapy (RT).
Methods:
Using optimized protocols that would permit non-necrotic, well-vascularized tumor growth in pleura, chest wall, peritoneum and flank, tumors were established in immunodeficient (NOD/SCID gamma) mice using mesothelioma or lung adenocarcinoma (LAC) cells. Tumor burden progression, MSLN-targeted CAR T-Cell accumulation at primary and distant tumors was monitored by noninvasive bioluminescence imaging (BLI) and tumor volume measurements.
Results:
A single dose of MSLN CAR T cells administered intrapleurally proliferated (Figure 1A left panel), circulated extrapleurally and accumulated at abscopal sites, including the lymph nodes, chest wall, peritoneum, and flank within 3-5 days, with subsequent T-cell proliferation at abscopal sites (Figure 1A right panel). Primary tumor-targeted, single-dose, thoracic RT prior to T-cell administration augmented T-cell accumulation as demonstrated by BLI (Figure 1B) and tumor T-cell quantification (p<0.01). In a mouse model of primary pleural, abscopal antigen-expressing and non-expressing flank tumors (Figure 1C), a single, low-dose, non-cytotoxic thoracic RT enhanced abscopal site CAR T-cell accumulation that resulted in tumor regression (p=0.01; Figure 1D). Figure 1
Conclusion:
Regionally administered mesothelin-targeted CAR T cells proliferate and eradicate the primary tumor, accumulate and demonstrate anti-tumor efficacy at abscopal sites prior to eradication of the primary tumor in an antigen-specific manner. A single low-dose primary tumor-targeted radiation therapy promotes scopal and abscopal anti-tumor efficacy. These results provide rationale to initiate a clinical trial of combination regional therapies with radiation therapy and CAR T cells.
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OA18 - New Insights in the Treatment of Thymic Malignancies (ID 408)
- Event: WCLC 2016
- Type: Oral Session
- Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
- Presentations: 1
- Moderators:N. Girard, S.B. Watzka
- Coordinates: 12/07/2016, 11:00 - 12:30, Schubert 2
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OA18.04 - Discussant for OA18.01, OA18.02, OA18.03 (ID 7044)
11:30 - 11:45 | Author(s): A. Rimner
- Abstract
- Presentation
Abstract not provided
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OA24 - Radiotherapy of Lung Cancer: Recent Developments (ID 411)
- Event: WCLC 2016
- Type: Oral Session
- Track: Radiotherapy
- Presentations: 1
- Moderators:K. Dieckmann, S. Rieken
- Coordinates: 12/07/2016, 14:20 - 15:50, Stolz 1
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OA24.06 - Histologic Subtype of Early-Stage Lung Adenocarcinoma is a Predictor of Failure Patterns after Stereotactic Body Radiation Therapy (ID 4618)
15:15 - 15:25 | Author(s): A. Rimner
- Abstract
- Presentation
Background:
Stereotactic body radiation therapy (SBRT) has emerged as an effective treatment for early-stage lung cancer. Histologic subtyping in surgically resected lung adenocarcinomas is recognized as a prognostic factor, with the presence of solid or micropapillary patterns predicting poor outcomes. Herein, we describe outcomes following SBRT for early-stage lung adenocarcinoma by histologic subtype.
Methods:
We identified 119 consecutive patients (124 lesions) with stage I-IIA lung adenocarcinoma who were treated with definitive SBRT at our institution between August 2008 and August 2015 and had undergone core biopsy. Histologic subtyping was performed according to the 2015 WHO Classification. Thirty-seven tumors (30%) were of high risk subtype, defined as containing a component of solid and/or micropapillary pattern. Cumulative incidences of local, nodal, regional and distant failure were compared between high risk vs. non-high risk adenocarcinoma subtypes with Gray’s test, and multivariable-adjusted hazard ratios were estimated from propensity score-weighted Cox regression models.
Results:
Median follow-up for the entire cohort was 17 months and 21 months for surviving patients. The 1-year cumulative incidence of local, nodal, regional and distant failure, respectively, in high risk and non-high risk lesions were 7.3%, 14.8%, 4.0%, 22.7% and 2.7%, 2.6%, 1.2%, 3.6%. Hazard ratios for local, nodal, regional and distant failure, respectively, of high risk lesions compared to non-high risk were 16.8 (95% CI 3.5-81.4), 3.8 (95% CI 0.95-15.0), 20.9 (95% CI 2.3-192.3), 6.9 (95% CI 2.2-21.1). No significant difference was seen with regard to overall survival.
Conclusion:
Outcomes following SBRT for early-stage adenocarcinoma of the lung are highly correlated with histologic subtype, with micropapillary and solid tumors portending significantly higher rates of locoregional and metastatic progression. In this context, histologic subtype based on core biopsies is a novel prognostic factor and may have important implications for patient selection, adjuvant treatment, biopsy methods and clinical trial design.
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P2.02 - Poster Session with Presenters Present (ID 462)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Locally Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.02-060 - SBRT and Sequential Chemotherapy for Stage IIA to IIIA Non-Small Cell Lung Cancer - A Phase I Dose Escalation Study (ID 5991)
14:30 - 14:30 | Author(s): A. Rimner
- Abstract
Background:
Stereotactic Body Radiation Therapy (SBRT) has become the standard of care for inoperable early-stage non-small cell lung cancer (NSCLC) due to excellent local control and survival outcomes. Its role in larger tumors is undefined, and patients with inoperable locally advanced NSCLC patients are treated with conventionally fractionated radiation therapy and chemotherapy. Our phase I dose escalation trial evaluates the maximum tolerated dose (MTD) of SBRT in patients with stage IIA to IIIA NSCLC involving a larger primary tumor and/or hilar involvement.
Methods:
Patients with inoperable stage IIA to IIIA (T2b-T4N0M0 and TanyN1M0) NSCLC fit for SBRT and sequential chemotherapy were eligible. SBRT dose escalation levels in a classic 3+3 design were 40Gy, 50Gy, and 60Gy in 5 fractions, delivered every other day. Platinum-based doublet chemotherapy was initiated 6 to 8 weeks after SBRT. The primary endpoint was the MTD based on SBRT-related acute (<3 months) ≥ grade 4 or persistent ≥ grade 3 toxicities (per Common Terminology Criteria for Adverse Events [CTCAE] v4.03). Patient reported outcomes were assessed using the NCI PRO-CTCAE questionnaire.
Results:
Nine patients were enrolled, three at the 40 Gy and six at the 50 Gy dose level. All patients received SBRT to the prescribed dose. Two patients receiving 50 Gy were no longer eligible for chemotherapy after SBRT. Median follow-up time was 6.3 months (range: 2.5 - 28.9). At the 40 Gy dose level, there was one patient with late (≥3 months post-SBRT) grade 3 pneumonia and one with late grade 3 bronchial obstruction. The dose was escalated to 50 Gy. At the 50 Gy dose level, two patients experienced persistent grade 3 radiation pneumonitis. One patient also had acute grade 4 respiratory insufficiency and contralateral pneumothorax. In the expanded 50 Gy cohort, one patient experienced persistent grade 3 nausea, vomiting, and abdominal pain, and another developed grade 3 chest wall pain. Therefore 50 Gy was determined to be the MTD. On PRO-CTCAE questionnaires patients most frequently reported fatigue (75%), dyspnea (50%), cough (38%), and pain (38%) as interfering “quite a bit” or “very much” with their daily activities.
Conclusion:
We determined that 50 Gy in five fractions followed by sequential chemotherapy is the MTD for SBRT in patients with stage IIA to IIIA NSCLC. Long-term outcomes and larger trials will be needed to assess whether SBRT results in superior local control and survival compared to conventional chemoradiation. Made possible by the generous support of the DallePezze Foundation
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P2.05 - Poster Session with Presenters Present (ID 463)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Radiotherapy
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.05-003 - PIK3CA Mutation is Associated with Increased Local Failure in Lung Stereotactic Body Radiation Therapy (SBRT) (ID 5251)
14:30 - 14:30 | Author(s): A. Rimner
- Abstract
Background:
Hyperactivation of the phosphatidylinositol-3-kinase (PI3K) pathway has been associated with radioresistance. It is unclear whether such mutations also confer suboptimal local control for patients who receive lung stereotactic body radiation therapy (SBRT). Our objective was to examine whether mutations in the EGFR/AKT/PIK3CA signaling pathway are associated with local failure (LF) after lung SBRT.
Methods:
We retrospectively reviewed 134 patients who underwent SBRT to primary or metastatic lung lesions from 2007-2015 for whom molecular testing data was available for EGFR, AKT, and PIK3CA genes. For tumors of lung origin (n=122), molecular testing data was included from the lung tumor. For metastatic tumors to the lung (n=12), molecular testing data from either a primary or metastatic tumor site was used. Association between clinical factors, including molecular mutation status, and LF was evaluated with Cox regression analysis. The Kaplan-Meier method was used to assess differences in LF rates based on PIK3CA mutation status.
Results:
The most common histology was adenocarcinoma (90%) among all tumors. Six patients (4%) had PIK3CA mutation, 31 patients (23%) had EGFR mutation, and one patient (0.7%) had AKT mutation. Median lesion size was 2.0 cm (range, 0.6–5.6 cm), median dose was 48 Gy (range 30–70 Gy), and median number of fractions was 4 (range, 3–10). Median follow-up was 20 months (range, 0.2–70 months). LF was observed for 16 patients (12%). Median time to local failure was 15 months (range, 7–31 months). On univariate analysis, PIK3CA mutation presence was associated with LF (HR 5.3 [95% CI 1.1-25.0], p=0.03), while tumor histology (adenocarcinoma vs. other), tumor size (≤2cm vs. >2cm), primary tumor site (lung vs. other), and EGFR or AKT mutation presence were not. By multivariate analysis, PIK3CA mutation trended toward association with LF (HR 5.0 [95% CI 1.0-25.3], p=0.051). At one year, probability of LF in lesions with PIK3CA mutations was 12.4% vs. 5.7% in lesions without mutations (p=0.02). Lesions with PIK3CA mutations were associated with a decreased time to LF (mean 17.9 months [95% CI 12.7–23.2 months]) compared to those without PIK3CA mutation (mean 58.6 months [95% CI 52.6–64.7 months]).
Conclusion:
We explored EGFR/AKT/PI3KCA pathway mutations and found that patients with PIK3CA mutations are at higher risk for LF after lung SBRT. Due to the limitation of small numbers, this data needs to be validated in a larger patient cohort. Nonetheless, this is a novel finding and hypothesis-generating for future studies.
