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Z. Liao

Moderator of

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    ES 10 - Radiation Treatment Update (ID 519)

    • Event: WCLC 2017
    • Type: Educational Session
    • Track: Radiotherapy
    • Presentations: 5
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      ES 10.01 - SBRT (ID 7624)

      14:30 - 16:15  |  Presenting Author(s): Billy Loo

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      ES 10.02 - IMRT (ID 7625)

      14:30 - 16:15  |  Presenting Author(s): Francoise Mornex

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      ES 10.03 - Proton Therapy (ID 7626)

      14:30 - 16:15  |  Presenting Author(s): Yong Chan Ahn

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      ES 10.04 - Carbon-ion Therapy (ID 7627)

      14:30 - 16:15  |  Presenting Author(s): Yuko Nakayama

      • Abstract
      • Presentation
      • Slides

      Abstract:
      Introduction Approximately 68 particle therapy facilities are in operation worldwide. Among them, only 11 offer carbon-ion treatment (5 in Japan, 2 in Germany, 2 in China, 1 in Italy, and 1 in Austria; 6 also offer proton), and the remainder offer proton treatment. More than 150,000 patients have been treated with particle therapy worldwide from 1954 to 2015, 87% of which were treated with protons and 13% with carbon-ions or other particles. (from the website of the Particle Therapy Co-Operative Group: http://www.ptcog.ch/). The National Institute of Radiological Sciences (NIRS) in Chiba, Japan, has been treating cancer with high-energy carbon-ions since 1994. The majority of patients curatively treated with carbon-ions worldwide were treated at NIRS (1). Through the data they have generated, carbon-ion radiotherapy (CIRT) for non-small cell lung cancer (NSCLC) has been suggested as safe and efficacious. Here, I review those results and discuss this modern technology. Characteristics of CIRT In comparison with photon radiotherapy, CIRT has better dose distribution to tumors while simultaneously minimizing dose to surrounding normal tissues. Moreover, CIRT offers potential advantages over protons, which have similar dose distribution benefits. Carbon-ions provide a better physical dose distribution, because lateral scattering is lessened, and offer a higher relative biological effectiveness with a lower oxygen enhancement ratio; desirable features for eradication of radioresistant, hypoxic tumors. This difference between densely ionizing nuclei and sparsely ionizing x-rays/protons further offers potential radiobiological advantages, such as reduced repair capacity in irradiated tumors, decreased cell-cycle dependence, and possibly stronger immunological responses. CIRT of early NSCLC Surgical resection with lobectomy has been the standard treatment of choice for early-stage NSCLC. From a Japanese lung cancer registry study of 11,663 surgical cases in 2004, overall survival (OS) rates at 5 years for stages IA and IB disease were 82.0% and 66.8%, respectively (2). Radiotherapy is an option for patients who are not suitable for surgery or refuse it. Recently, hypofractionated radiotherapy is regarded as an alternative for surgery in cases of localized NSCLC, employing x-ray stereotactic body radiotherapy, protons, or CIRT. Regarding CIRT, for peripheral stage I NSCLC, the number of fractions delivered per treatment at NIRS has been reduced through consecutive trials from 18 to 9, then 4, and finally to a single fraction (3-7). This latest result , conducted via dose escalation study, was recently reported by NIRS, demonstrating results comparable to those with previous fractionated regimens (8). The Japan Carbon-ion Radiation Oncology Study Group (J-CROS) has further reported that the results of a multi-institutional retrospective study of CIRT for stage I NSCLC were similar with the results of previous single institutional reports (9). The results of CIRT in stage IA NSCLC are similar to the best stereotactic body radiotherapy results reported worldwide. For stage IB disease, CIRT results appear tentatively superior to those reported for photon stereotactic body radiotherapy in terms of local control and lung toxicity, but will require randomized controlled trials to verify. Despite this high local control, however, disease-specific survival is much lower in stage IB than in stage IA, due to distant metastatic recurrence. A combination of CIRT with systemic therapy is therefore essential to improve survival. CIRT demonstrates a better dose distribution than both SBRT and proton therapy in most cases of early-stage lung cancer. Therefore, CIRT may be safer for treating patients with adverse conditions such as large tumors, central tumors, and poor pulmonary function. CIRT of locally advanced NSCLC There has only been one report regarding CIRT for locally advanced NSCLC. A prospective nonrandomized phase I/II study of carbon-ion therapy in a favorable subset of locally advanced NSCLC was reported from NIRS (10). They showed that short-course carbon-ion monotherapy (72GyE/16Fr) was associated with manageable toxicity and encouraging local control rates. Among them, cT3-4N0M0 patients were particularly favorable candidates for CIRT. However, there is a relative dearth of evidence for CIRT in the setting of locally advanced NSCLC, and more trials, including those combined with systemic immunological or chemotherapy agents, are required. Future directions We have organized a multi-institutional study group of carbon-ion radiation oncology in Japan (J-CROS) and have been conducting a number of trials involving a multitude of tumor sites. A number are emerging as particularly attractive for CIRT with possibility of new levels of achievable disease control, including in NSCLC, head and neck cancer, locally advanced unresectable pancreatic cancer, hepatocellular carcinoma, locally recurrent rectal cancer, as well as others. The outcomes of CIRT for stage I NSCLC in Japanese multi-institutional datasets were retrospectively analyzed. As a result, CIRT is considered a low-risk and effective treatment option for patients with stage I NSCLC. Confirmative multi-institutional prospective studies via J-CROS began last year, so as to validate these results. References: 1. Kamada T, Tsujii H, Blakely EA, et al. Carbon ion radiotherapy in Japan: an assessment of 20 years of clinical experience. Lancet Oncol 2015; 16: e93-100. 2. Sawabata N, Miyaoka E, Asamura H, et al. Japanese lung cancer registry study of 11,663 surgical cases in 2004: demographic and prognosis changes over decade. J Thorac Oncol 2011; 6: 1229-35. 3. Miyamoto T, Yamamoto N, Nishimura H, et al. Carbon ionradiotherapy for stage I non-small cell lung cancer. Radiother Oncol 2003; 66: 127-140. 4. Miyamoto T, Baba M, Yamamoto N, et al. Curative treatment of Stage I non-small-cell lung cancer with carbon ion beams using a hypofractionated regimen. Int J Radiation Oncol Biol Phys 2007; 67: 750-758. 5. Miyamoto T, Baba M, Sugane T, et al. Carbon ion radiotherapy for stage I non-small cell lung cancer using a regimen of four fractions during 1 week. J Thorac Oncol 2007; 10: 916-926. 6. Sugane T, Baba M, Imai R, et al. Carbon ion radiotherapy for elderly patients 80 years and older with stage I non-small cell lung cancer. Lung Cancer 2009; 64: 45-50. 7. Karube M, Yamamoto N, Nakajima M, et al. Single-fraction carbon-ion radiation therapy for patients 80 years of age and older with stage I non-small cell lung cancer. Int J Radiation Oncol Biol Phys 2016; 95: 542-548. 8. Yamamoto N, Miyamoto T, Nakajima M, et al. A dose escalation clinical trial of single-fraction carbon ion radiotherapy for peripheral stage I non–small cell lung cancer. J Thorac Oncol 2016; 12: 673-680. 9. Shioyama Y, Yamamoto N, Saito J-i, et al. Multi-institutional retrospective study of carbon ion radiation therapy for stage I non-small cell lung cancer: Japan Carbon Ion Radiation Oncology Study Group. Int J Radiation Oncol Biol Phys 2016; 96: S10. 10. Takahashi W, Nakajima M, Yamamoto N, et al. A prospective nonrandomized phase I/II study of carbon ion radiotherapy in a favorable subset of locally advanced non-small cell lung cancer (NSCLC). Cancer 2015; 121: 1321-7.

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      ES 10.05 - RT and Targeted Therapies (ID 7865)

      14:30 - 16:15  |  Presenting Author(s): Rafal Dziadziuszko

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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Author of

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    MA 01 - SCLC: Research Perspectives (ID 650)

    • Event: WCLC 2017
    • Type: Mini Oral
    • Track: SCLC/Neuroendocrine Tumors
    • Presentations: 1
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      MA 01.03 - The Potential of ctDNA Sequencing in Disease Monitoring and Depicting Genomic Evolution of Small-Cell Lung Cancer Under Therapy (ID 9682)

      11:00 - 12:30  |  Author(s): Z. Liao

      • Abstract
      • Presentation
      • Slides

      Background:
      Although small cell lung cancer (SCLC) is sensitive to initial therapy, almost all patients relapse and survival remains poor. Outgrowth of treatment-resistant subclones could be responsible for recurrence. However, genomic evolution of SCLC after treatment hasn’t been well investigated, partially due to the challenge of obtaining longitudinal samples. CT is the standard modality for response assessment and disease monitoring. But it doesn’t always accurately assess the disease status. SCLC is characterized by early hemagenous spread, which makes circulating tumor DNA (ctDNA) analysis a promising modality for genomic profiling and disease monitoring of SCLC.

      Method:
      Targeted-capture deep sequencing (mean target coverage 538x-1866x) of 545 cancer genes was performed to 44 ctDNA samples collected before therapy as baseline and at different timepoints during treatment from 23 SCLC patients. Pretreatment tumor biopsies from 8 patients were also sequenced (mean target coverage 348x-1281x) of the same gene panel. DNA from peripheral blood mononuclear cells was served as the germline control.

      Result:
      Mutations were identified in all 44 ctDNA samples with a median of 16 mutations per sample (average mutation burden of 6.6/Mb). TP53 and RB1 were the most frequently mutated genes, detected in 91% (21/23) and 65% (15/23) patients, respectively. 74 mutations were identified from the 8 tumor biopsies, among which, 69 (93.2%) were detected in matched ctDNA. We inferred subclonal architecture of each ctDNA sample based on cancer cell fraction derived using PyClone. A median of 10 (ranging 2-26) subclones was inferred from each ctDNA sample and only 17% (2% to 60.%) of mutations were clonal mutations suggesting substantial genomic heterogeneity. Single gene mutations were not associated with survival. However, mean variant allele frequency of clonal mutations (clonal-VAF) at baseline was associated with progression-free survival (PFS) and overall survival (OS) independent of stage, age, or platinum sensitivity. The median PFS of patients with higher versus lower than median clonal-VAF was 5.2 months (95% CI, 4.6 to 5.8 months) versus 10.0 months (95% CI, 9.3 to 10.7 months), p=0.002. The median OS was 8.1 months (95% CI, 5.5 to 10.7 months) versus 24.9 months (95% CI, 0.0 to 51.2 months) in patients with higher versus lower than median clonal-VAF, respectively, p=0.004. Analysis of serial ctDNA before and during treatment showed that clonal-VAF closely tracked closely with treatment responses.

      Conclusion:
      ctDNA sequencing is a promising modality for genomic profiling and disease monitoring for SCLC patients. Clonal VAF may be a better ctDNA metric than single gene mutations.

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    OA 01 - The New Aspect of Radiation Therapy (ID 652)

    • Event: WCLC 2017
    • Type: Oral
    • Track: Radiotherapy
    • Presentations: 1
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      OA 01.07 - Tracking Major Symptom Burden from Chemotherapy Concurrent with 3D vs. IMRT vs. Proton Beam Radiotherapy for NSCLC (ID 9443)

      11:00 - 12:30  |  Author(s): Z. Liao

      • Abstract
      • Presentation
      • Slides

      Background:
      During standard concurrent chemoradiotherapy (CRT), patients with NSCLC often report severe symptoms that should be routinely assessed and managed. According to the United States FDA specified standards, patient-reported outcome (PRO) instruments used in clinical trials should have good measurement properties of reliability, validity, and the ability to detect change. This quantitative study used a validated PRO symptom-assessment tool, the MD Anderson Symptom Inventory-Lung Cancer (MDASI-LC), to compare a cluster of CRT-related symptoms in NSCLC patients receiving CRT, and to investigate the sensitivity of a composite score of these symptoms.

      Method:
      We enrolled patients with locally advanced NSCLC (n=118) who underwent intensity-modulated radiation therapy (IMRT, n=33), 3-dimensional conformal radiation therapy (3DCRT, n=22), or proton-beam therapy (PBT, n=63). Patients completed the MDASI-LC weekly for up to 12 weeks. Two criteria used for item selection to form a subscale for CRT-related symptoms: MDASI-LC items rated 4-10 in >25% of observations, and that increased significantly during therapy (by mixed-effect models). A CRT-symptom score (MDASI-LC-CRT) was generated by averaging scores from those symptoms. The MDASI-LC-CRT’s responsiveness to treatment was examined by within-person change over time and effect size (ES) statistics.

      Result:
      Six symptoms—pain, fatigue, drowsiness, lack of appetite, sore throat, coughing—were identified as the most-severe CRT-related symptoms during and after therapy. Before CRT, MDASI-LC-CRT scores did not differ by treatment (3DCRT 2.2±1.8, IMRT 1.6±1.5, PBT 1.8±1.7, p=0.329). At the end of CRT, MDASI-LC-CRT was highest for 3DCRT (4.85±2.40), followed by IMRT (3.18±1.85) and PBT (2.29±1.65). A large ES (1.24) was found for 3DCRT vs. PBT; medium ES were found for 3DCRT vs. IMRT (0.78) and IMRT vs. PBT (0.51). The ES for pre-CRT vs. post-CRT difference (1.8±1.7 vs. 3.0±2.1) was medium (0.63) for all patients, large for 3DCRT (1.25) and IMRT (0.93), and small for PBT (0.28). The MDASI-LC-CRT score increased significantly over treatment (estimated weekly increase=0.21, p<0.0001), peaking at week 7 (95%CL=6.2-7.8, p<.0001) and then decreasing to week 12 (est=0.18, p=0.001). Significantly larger weekly increase was reported by 3DCRT and IMRT patients, compared with PBT patients (all p<0.0001).

      Conclusion:
      The MDASI-LC-CRT is a sensitive indicator of dynamic change in major symptom burden during CRT. This subscale could be routinely used for symptom monitoring while patients are going through CRT and appropriate supportive measures could be instituted early. PBT was the best tolerated of the radiation modalities when given concurrently with chemotherapy with the least worsening of symptoms over the CRT period.

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