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Fiona Hegi-Johnson
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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: 1
- Now Available
- Moderators:Maria Werner Wasik, Alexandra Giraldo
- Coordinates: 9/09/2019, 11:00 - 12:30, Dublin (1997)
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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.
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P2.16 - Treatment in the Real World - Support, Survivorship, Systems Research (ID 187)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Treatment in the Real World - Support, Survivorship, Systems Research
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.16-33 - What Influences Patient Decision-Making About Lung-Cancer Treatment? A Discrete Choice Experiment (Now Available) (ID 485)
10:15 - 18:15 | Presenting Author(s): Fiona Hegi-Johnson
- Abstract
Background
Despite major advances in radiotherapy, surgery remains the treatment of choice for patients with stage I non-small cell lung cancer. We sought to investigate what influenced preferences for surgery or SABR among cancer patients.
Method
Using a discrete choice experiment (DCE) survey, we asked cancer patients to choose between lung cancer treatment options described by: type of treatment, chance of being cancer free for 12 months, chance of experiencing life threatening complications, chance of ongoing complications, impact on usual activities, who recommended treatment, whether treatment is usual care and out-of-pocket (OOP) costs. Each respondent completed nine choice questions. Choices were analysed using latent class analysis.
Result
A total of 204 responses were received (57% female). Of these, 20 reported a diagnosis of lung cancer; the rest had been diagnosed with other cancers, including 53 with melanoma. Overall, the chance of being without cancer was considered the most important attribute and costs the least. The latent class analysis identified three groups: Group 1 (21%) was focussed on costs and the doctor’s recommendation; Group 2 (60%) focused on the intervention (with a preference for surgery over radiotherapy), efficacy, side effects, functioning, doctor’s recommendation and the highest level of OOP costs; Group 3 members (19%) were focused on the doctor’s recommendation only. Women are more likely to be in Group 1 relative to 3, and those with higher educational attainment are more likely to be in Group 2 than 3. A more substantive analysis showed further differences between groups in terms of their tumour status, gender, educational attainment and health-care card status.
Conclusion
The results of this study show that a doctor’s recommendation is a vital factor in patients’ decision-making. The importance of this finding is emphasised by the fact that Group 2, representing 60% of respondents, preferred surgery over radiotherapy. Advocates of radiotherapy as a curative intervention for lung cancer need to educate doctors as well as patients about its potential side-effects, benefits and costs.
