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Alexandra Giraldo
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ES16 - Modern Radiotherapy in Stage III NSCLC (ID 19)
- Event: WCLC 2019
- Type: Educational Session
- Track: Treatment of Locoregional Disease - NSCLC
- Presentations: 4
- Now Available
- Moderators:Maria Werner Wasik, Alexandra Giraldo
- Coordinates: 9/09/2019, 11:00 - 12:30, Dublin (1997)
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ES16.01 - Proton Therapy (Now Available) (ID 3242)
11:00 - 12:30 | Presenting Author(s): Corinne Faivre-Finn
- Abstract
- Presentation
Abstract
Proton therapy is an attractive option for the treatment of lung cancer patients due to the physical properties of proton beams. Proton therapy allows a focused delivery of radiation at the Bragg peak, with very steep decline of the radiation dose beyond the target volume. These properties offer the possibility to 1) reduce toxicity by reducing the integral dose and the dose to adjacent normal tissues and 2) escalate the dose to the target in some patients.
In this talk, I will summarise briefly the physics/radiobiology of protons and the need for adaptation. I will also discuss the rationale for the use of protons in patients with lung cancer, including reduction in integral dose, cardiac toxicity and reduction in haematological toxicity. The clinical trial evidence supporting the use of protons will be presented in early stage and locally advanced non-small cell lung cancer as well as in small-cell lung cancer.
Finally I will discuss future research directions, including preclinical and drug-proton combination research, ongoing clinical trials, the model based-approach and the need for biomarkers.
REFERENCES
Liao Z, Lee JJ, Komaki R, eat l. Bayesian Adaptive Randomization Trial of Passive Scattering Proton Therapy and Intensity-Modulated Photon Radiotherapy for Locally Advanced Non-Small-Cell Lung Cancer. J Clin Oncol. 2018;36(18):1813-1822
Chang JY, Jabbour SK, De Ruysscher D, et al; International Particle Therapy Co-operative Group Thoracic Subcommittee.Consensus Statement on Proton Therapy in Early-Stage and Locally Advanced Non-Small Cell Lung Cancer. Int J Radiat Oncol Biol Phys. 2016;95(1):505-16.
Vyfhuis MAL, Onyeuku N, Diwanji T, Mossahebi S, Amin NP, Badiyan SN, Mohindra P, Simone CB 2nd. Advances in proton therapy in lung cancer. Ther Adv Respir Dis. 2018 Jan-Dec;12:1753466618783878
C, Pawelke J, Seidlitz A, Peitzsch C, et al; “Radiobiology of Proton Therapy”: Results of an international expert workshop.Lühr A, von Neubeck Radiother Oncol. 2018; 128(1):56-67
Jin, J.Y., et al., Higher Radiation Dose to Immune System is Correlated With Poorer Survival in Patients With Stage III Non-small Cell Lung Cancer: A Secondary Study of a Phase 3 Cooperative Group Trial (NRG Oncology RTOG 0617). International Journal of Radiation Oncology Biology Physics, 2017. 99(2): p. S151-S152.
Joseph, N., et al., Post-treatment lymphocytopaenia, integral body dose and overall survival in lung cancer patients treated with radical radiotherapy. Radiotherapy and Oncology, 2019. 135: p. 115-119.
Durante, M., D.J. Brenner, and S.C. Formenti, Does Heavy Ion Therapy Work Through the Immune System? Int J Radiat Oncol Biol Phys, 2016. 96(5): p. 934-936.
Lee, H.J., Jr., J. Zeng, and R. Rengan, Proton beam therapy and immunotherapy: an emerging partnership for immune activation in non-small cell lung cancer. Translational lung cancer research, 2018. 7(2): p. 180-188.
Dess, R.T., et al., Cardiac Events After Radiation Therapy: Combined Analysis of Prospective Multicenter Trials for Locally Advanced Non-Small-Cell Lung Cancer. J Clin Oncol, 2017. 35(13): p. 1395-1402.
McWilliam, A., et al., Radiation dose to heart base linked with poorer survival in lung cancer patients. Eur J Cancer, 2017. 85: p. 106-113.
Schulz-Ertner, D. and H. Tsujii, Particle radiation therapy using proton and heavier ion beams. J Clin Oncol, 2007. 25(8): p. 953-64.
Gameiro, S.R., et al., Tumor Cells Surviving Exposure to Proton or Photon Radiation Share a Common Immunogenic Modulation Signature, Rendering Them More Sensitive to T Cell-Mediated Killing. Int J Radiat Oncol Biol Phys, 2016. 95(1): p. 120-30.
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ES16.02 - MRI-Based Radiotherapy (Now Available) (ID 3243)
11:00 - 12:30 | Presenting Author(s): Fiona McDonald
- Abstract
- Presentation
Abstract
One key potential advance for radical radiotherapy indications in lung cancer is the integration of magnetic resonance imaging (MRI) in the treatment pathway, giving anatomical and functional detail without additional radiation exposure to the patient. Incorporating anatomical MRI into the treatment planning may improve target volume and organs at risk delineation reproducibility. Functional MRI may facilitate heterogeneous dosing of target volumes and assessment of normal tissue toxicity to assist adaptive strategies. Four-dimensional MRI has the potential to complement 4D CT and 4D F-18-FDG PET with superior spatial resolution. MR-guided radiotherapy delivery machines are increasing in number internationally, providing novel hybrid technology that continues to evolve with various technical challenges to overcome. It is anticipated that the clinical benefits of MR-guided radiotherapy will lie the ability to adapt treatment in real-time. Research is ongoing to develop trials of MR-guided adaptive treatment schedules in lung cancer patients.
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ES16.03 - Optimal Integration of Radiotherapy, TKIs and I/O (Now Available) (ID 3244)
11:00 - 12:30 | Presenting Author(s): Umberto Ricardi
- Abstract
- Presentation
Abstract
Umberto Ricardi, Serena Badellino, Cristina Mantovani, Donatella Caivano, Stefania Martini, Marzia Cerrato, Giuseppe Carlo Iorio
Department of Oncology, University of Turin, Italy
Approximately one third of patients affected by non-small cell lung cancer (NSCLC) present with ‘locally advanced’ disease at diagnosis. Most patients are considered inoperable due to disease extension, and chemo-radiotherapy (CT-RT) still represents the standard therapeutic option, with unsatisfactory results in terms of overall survival (OS) despite advances in staging and technological evolution in radiation therapy planning and delivery. Besides radiation dose escalation, a logical step for improving survival in inoperable stage III patients was to evaluate the combination of concurrent/sequential RT-CT with targeted agents (tyrosine kinase inhibitors, TKI; mono-clonal antibody against EGFR; ALK/ROS1 inhibitors) and/or anti- angiogenic therapies, following the positive results obtained in stage IV disease (1, 2). Since the early 2000s, when first-generation TKIs were first approved for clinical use, several studies have been conducted in an attempt to demonstrate the efficacy of targeted therapies combined with radiotherapy (3, 4, Table 1). These studies were testing mainly the feasibility and the tolerability of this combination, with not statistical significant benefit in terms of outcomes (4, Table 1). Mature results of an international trial testing the contribution of TKIs with chemoradiotherapy in patients affected with stage III NSCLC harboring sensitive mutations are still waited.
Immunotherapy, and in particular immune-checkpoint inhibitors targeting the PD-1/PD-L1 axis, gained wide popularity for NSCLC in light of the positive findings of several trials in metastatic disease (1, 5). Radiation therapy combined with immunotherapy represent a new therapeutic opportunity, given the role of RT in reversing immunosuppressive barriers within the tumor microenvironment (6). The growing enthusiasm for immune-oncology and its possible applications in radiation oncology led to a remarkable expansion of pre-clinical and clinical studies testing various combinations of immunotherapeutic agents and radiation. Stage III unresectable NSCLC is an interesting setting for the combined use of chemo-radiation and immunotherapy, also considering the multiple experimental evidences in favor of a synergistic effect between radiation and immune checkpoint inhibitors, with the potential of enhancing immuno-modulating effects and overcoming resistance. The PACIFIC trial (PD-L1 inhibitor Durvalumab vs placebo, unresectable stage III NSCLC who did not progress following concurrent platinum-based chemo-radiotherapy) showed a major improvement in 2-year PFS and OS, which holds promise for an improved cure rate (7). Even the use of Pembrolizumab (anti-PD-1 agent) is under investigation in a series of trials. A number of studies (e.g. INSPIRE study) investigated the role of Tecemotide (anti-tumor vaccine inducing a specific immune response against MUC-1, glycoprotein overexpressed in NSCLC) (8) in Stage III NSCLC. More evidence is awaited regarding the optimal timing when combining immunotherapy and CT-RT, considering the possibility to improve this synergism even further. Several ongoing trials are testing multiple schedules (5). A predominance of the consolidation/adjuvant/maintenance setting is evident, however many studies also integrated immunotherapy at the beginning of chemo-radiation. The latter schedule should be one of the most efficient ways to fully harness the synergistic effects of chemo-radiation and immunotherapy in terms of boosting the immune-stimulating effects, particularly when using anti-PD-L1 agents, given that enhanced expression of PD-L1 during RT may be one of the main causes of radioresistance. Some attention should also be paid to those trials introducing anti-PD-1 agents before chemo-radiation, as neo-adjuvant: this innovative approach could be promising, by integrating radio-chemotherapy in a tumor micro-environment already modified by immunomodulators, and with a subsequent consolidation phase. When using anti-PD-L1 agents in this setting, PD-L1 expression levels would probably be necessary to stratify patients as highlighted in the PACIFIC trial post-hoc analysis (9).
REFERENCES
Filippi AR, Di Muzio J, Badellino S, Mantovani C, Ricardi U. Locally-advanced non-small cell lung cancer: shall immunotherapy be a new chance? J Thorac Dis 2018;10(Suppl 13):S1461-S1467. doi: 10.21037/jtd.2017.12.53.
Planchard D, Popat S, Kerr K, Novello S, Smit EF, Faivre-Finn C, et al. Metastatic non-small cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2019 Jan 30. doi: 10.1093/annonc/mdy474.
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Arcangeli S, Jereczek-Fossa BA, Alongi F, Aristei C, Becherini C, Belgioia L, Buglione M, et al. Combination of novel systemic agents and radiotherapy for solid tumors - Part II: An AIRO (Italian association of radiotherapy and clinical oncology) overview focused on treatment toxicity. Crit Rev Oncol Hematol. 2019;134:104-119. doi: 10.1016/j.critrevonc.2018.11.006.
Kordbacheh T, Honeychurch J, Blackhall F, Faivre-Finn, Illidge. Radiotherapy and anti-PD-1/PD-L1 combinations in lung cancer: building better translational research platforms. Ann Oncol. 2018 Feb 1;29(2):301-310. doi: 10.1093/annonc/mdx790.
Formenti SC, Demaria S. Systemic effects of local radiotherapy. Lancet Oncol. 2009 Jul;10(7):718-26. doi: 10.1016/S1470-2045(09)70082-8.
Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, et al. Overall Survival with Durvalumab after Chemoradiotherapy in Stage III NSCLC. N Engl J Med 2018; 379:2342-2350 DOI: 10.1056/NEJMoa1809697.
Wu YL, Park K, Soo RA, et al. INSPIRE: A phase III study of the BLP25 liposome vaccine (L-BLP25) in Asian patients with unresectable stage III non-small cell lung cancer. BMC Cancer 2011;11:430.
Kim YH. Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. N Engl J Med. 2019 Mar 7;380(10):989-990. doi: 10.1056/NEJMc1900407.
Table 1. Major studies on Radiotherapy and TKIs in LA-NSCLC.
Author and year
Study type
Number of patients
RT technique/ dose/ fractionation
Combination (concomitant, other)
Primary Endopoint
Treatment outcome
Martinez et al (2016)
Phase II Randomised, NSCLC
90
3D-CRT 66 Gy/33 fx
RT alone vs RT+Erlotinib
Feasibility/Tolerabily
Median OS: 11.4 vs 8.9 (p=0.835)
Lilenbaum et al (2015)
Phase II, unresectable NSCLC
75
3D-CRT 66 Gy/33 fx
Induction Carbo/Paclitaxel® RT+ Erlotinib
OS
Median OS: 17 months. 1-yy OS: 57%
Ramella et al (2013)
Phase I-II, unresectable NSCLC
60
3D-CRT 59.4 Gy/33 fx
CT-RT+Erlotinib
Feasibility/Tolerabily
Median OS:23.3months. Median PFS: 4.7 months
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ES16.04 - Molecular Biology of Radiation Toxicity (Now Available) (ID 3245)
11:00 - 12:30 | Presenting Author(s): Fiona Hegi-Johnson
- Abstract
- Presentation
Abstract
Molecular Biology of Radiation Toxicity
Radiotherapy causes damage to normal and malignant cells, resulting in the cell death of tumour cells and radiation toxicity. Historically, the damage caused by radiotherapy has been described by the linear quadratic(LQ) model; a model of cellular survival derived by observing the effects of fractionated radiotherapy on cell cultures. However, it is increasingly understood that radiation toxicity is a complex event mediated by both the DNA damage modelled in the LQ model, and contributory factors such as immune and inflammatory upregulation and vascular dysfunction (see Figure 1). In this talk we will review the role of DNA damage immune and inflammatory mediated reactions on the development of radiation toxicity.
DNA damage and cell death
Radiotherapy effects damage on normal cells by both direct and indirect means. Direct damage to DNA by either secondary electrons or reactive oxygen species (ROS) causes the initiation of DNA damage responses (DDR). This can result in varying effects depending on individual variation in the efficiency of the DDR pathways, the severity of the insult, and the type of normal cell (2). For example, haematological cell death is usually mediated through primary apoptosis within a few hours of exposure; the majority of non-haematological cells die when they enter mitosis inappropriately (mitotic catastrophe).
Several key mediators of DDR have been identified. The 2 most important genetic modulators of DDR appear to be TP53, which mediates cell cycle arrest, facilitating both apoptosis and mitotic catastrophe, and ATM, which encodes the main kinase responsible for repairing double-strand DNA breaks (3). P53 works through downstream targets such as PUMA and p21, with evidence suggesting that different pathways are significant in different systems. In murine models of GI induced radiation toxicity, loss of PUMA is protective, whilst p53 and p21 loss increases toxicity (4). In contrast, in slowly replicative systems, such as the CNS and salivary glands, non-lethal radiation dose induced p53 activation may result in cell cycle arrest and altered differentiation (1); the survival of these damaged cells may lead to stem cell ageing and second malignancies.
Immune and Inflammatory system upregulation during radiotherapy and the impact on radiation toxicity
Radiotherapy exposure results in global upregulation of the immune system, increasing immune activity by increasing tumour cell-surface expression of major histocompatibility complex (MHC) class 1, increasing expression of tumour-associated antigens, activating dendritic cells, and changing the T cell repertoire, with a consequent reduction in the immune suppressive regulatory T-cells and an increase in active CD8 populations (5). These responses underpin the positive outcomes seen in immunoradiotherapy trials, but the relationship between radiotherapy and the immune system is likely to have complex effects both on tumour control and radiation toxicity.
Under normal circumstances dying cells are phagocytosed by macrophages and an anti-inflammatory pathway mediated by IL-10, TGF-b, platelet-activating factor, and prostaglandin E2 (PGE2) suppresses inflammation (6). During radiation the high levels of DNA damage results in the release of a high concentration of pro-inflammatory “damage-associated molecular patterns”(DAMPS) including oxidized DNA , adenosine triphosphate (ATP) heat shock proteins (HSPs) and high -mobility group box 1 (HMGB1)(7), leading to upregulation of inflammatory pathways through activation of TLR’s and triggering of pro-inflammatory cytokine cascades (8). This acute inflammatory reaction contributes to several of the hallmarks of acute radiation toxicity, including erythema, ulceration and oedema (9).
Finally, chronic inflammatory responses induced by radiotherapy contribute to radiation fibrosis; a result of imbalance in the creation and destruction of extracellular matrix components mediated by the upregulation of pro-inflammatory cytokines (TNFα, IL1, IL-4, IL6) and fibrogenic cytokines (TNFβ) (10).
Summary
Our understanding of the molecular biology of radiation toxicity continues to evolve, but is increasingly seen to be the result of the complex interplay of dysregulated DDR, immune and inflammatory responses. These pathways will provide a rich source of future therapies to increase both the efficacy and safety of radiotherapy treatment.
References
De Ruysscher D, Niedermann G Burnet N Siva S, Lee A, Hegi-Johnson F. Radiotherapy Toxicity, Nature Reviews Disease Primers (2019) 5:13
Lomax M, Folkes L, O’Neill P. 2013. Biological consequences of radiation induced DNA damage: relevance to radiotherapy. Clin Oncol (R Coll Radiol). 25:578–585.
Morgan, M. A. & Lawrence, T. S. Molecular pathways: overcoming radiation resistance by targeting DNA damage response pathways. Clin Cancer Res 21: 2898-2904 (2015).
Qiu, W. et al. PUMA regulates intestinal progenitor cell radiosensitivity and gastrointestinal syndrome. Cell Stem Cell 2, 576–583 (2008)
Vanpouille-Box, C. et al. DNA exonuclease Trex1regulates radiotherapy-induced tumour immunogenicity. Nat. Commun. 8, 15618 (2017).
Chung EY, Kim SJ, Ma XJ. 2006. Regulation of cytokine production during phagocytosis of apoptotic cells. Cell Res; 16: 154-161.
Gehrke N, Mertens C, Zillinger T, Wenzel J, Bald T, Zahn S, T€uting T, Hartmann G, Barchet W. 2013. Oxidative damage of DNA confers resistance to cytosolic nuclease TREX1 degradation and potentiates STING-dependent immune sensing. Immunity 39:482–495.
Piccinini A, Midwood K. 2010. DAMPening inflammation by modulating TLR signalling. Mediat Inflamm. 2010:672395.
Sprung et al 2015. Immmunological markers that predict radiation toxicity. Cancer Lett 368:191-197
Yamada M, Kubo H, Ota C, Takahashi T, Tando Y, Suzuki T, Fujino N, Makiguchi T, Takagi K, Suzuki T. 2013. The increase of microRNA-21 during lung fibrosis and its contribution to epithelial-mesenchymal transition in pulmonary epithelial cells. Respir Res. 14:95.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
