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P. Van Houtte

Moderator of

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    MS01 - Radiation as a Systemic Therapy (ID 18)

    • Event: WCLC 2013
    • Type: Mini Symposia
    • Track: Radiation Oncology + Radiotherapy
    • Presentations: 4
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      MS01.1 - Immunomodulation with Radiotherapy (ID 457)

      14:05 - 14:25  |  Author(s): Q. Le

      • Abstract
      • Slides

      Abstract
      Non-small cell lung cancer (NSCLC) is a highly lethal disease. Despite dose escalation with conformal radiotherapy (RT) in combination with modern chemotherapy, there is still a significantly high rate of intrathoracic failure and poor overall survival in patients with locally advanced disease. Recently, clinical studies have shown that blocking the immune check points such as CTLA4 and PD1 is effective in patients with metastatic NSCLC, resulting in a high response rate and improved both progression-free and overall survival. This generates enthusiasm for further studying the effect of immunomodulation with radiation therapy in earlier stage tumors. However, radiation can cause lymphodepletion, and persistently profound radiation-associated lymphopenia has been linked to poorer tumor control and survival in several solid tumors, including NSCLC. Radiation-induce lymphopenia can potentially counteract the effect of immunotherapy, making it less effective in patients treated with radiotherapy. Unfortunately the mechanism of radiation-induced lymphopenia is poorly understood, and unless we can overcome such effect, it will be difficult to integrate immunotherapy with radiotherapy. Galectin-1 (Gal-1) is a secreted carbohydrate binding lectin that is well known for its role in modulating T-cell homeostasis. More recently, it has been shown to play a major role in cancer progression. It is expressed in many cancers, including NSCLC, where increased Gal-1 expression is closely associated with larger tumors, more nodal metastasis and lower overall survival. In human head and neck cancer, expression of Galectin-1 was inversely related to intratumoral T-cell level and correlated with prognosis. We have previously showed that Gal-1’s secretion is enhanced by both hypoxia and radiation in NSCLC. Using an immunocompetent mouse model, we have also shown that tumor-derived Gal-1 is important for promoting tumor growth and spontaneous metastasis in NSCLC. Further mechanistic studies suggested that Gal-1 mediates its tumor promoting function by enhancing intratumoral T-cell death while protecting hypoxic tumor cells from apoptosis. More recently, using the same mouse model, we found that circulating plasma tumor Gal-1, which is elevated after tumor irradiation, appears to mediate the phenomenon of lymphopenia in mice. In addition, in vitro and in vivo studies indicate that down regulation of Gal-1 expression or blocking its function result in enhanced radiation sensitivity in NSCLC, resulting in more cell kill and tumor shrinkage. Based on these data, we believe that the poor outcome associated with radiation-induced lymphopenia is due to Gal-1’s effect on tumor infiltrating lymphocytes, and it is therefore logical to target Gal-1 in combination with radiation in NSCLC.

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      MS01.2 - Circulating Tumour Cells as a Mechanism of Radio Resistance (ID 458)

      14:25 - 14:45  |  Author(s): M. Macmanus

      • Abstract
      • Slides

      Abstract not provided

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      MS01.3 - Hypoxia as a Cause of Treatment Failure in NSCLC (ID 459)

      14:45 - 15:05  |  Author(s): O.T. Brustugun

      • Abstract
      • Slides

      Abstract
      Hypoxia as a cause of treatment failure in NSCLC Odd Terje Brustugun, MD PhD Senior Consultant, The Norwegian Radium Hospital, Oslo, Norway & Assoc. professor, Faculty of Medicine, University of Oslo, Oslo, Norway Well-oxygenated tumors respond better to various therapies than hypoxic tumors. Hypoxia is therefore a predictive factor. However, emerging knowledge has underscored that hypoxia is also a prognostic factor, independently of therapy, and that hypoxia in a tumor’s microenvironment induces a more aggressive tumor phenotype. Here, factors involved in hypoxia-mediated therapeutic failures will be discussed both in the context of therapy resistance and as a tumor biology phenomenon per se. Most tumors (including lung cancer) have a low pO~2~ of 0-7.5 mmHg which can be measured indirectly using tracers as 18F-FAZA PET imaging, or via MR-based techniques. However, due to the heterogenous distribution and temporal instability of hypoxia, such methods are limited by lack of resolution. Oxygen molecules diffuse freely in normal tissues, with a diffusion range of ca 200 um. However, all solid tumors over 1 cm[3] contain hypoxic regions due to several factors: abnormal microvessel structure and function leading to increased diffusion distance from vessel to cell, increased oxygen demand due to increased cellular proliferation, reduced oxygen supply due to vascular constriction and increased interstitial pressure. Anemia, frequently observed in cancer patients, adds to the reduced oxygen supply (1). Radiation kills cells mainly via production of free radicals that bind to DNA and induce strand breaks. Oxygen stabilizes the chemical bond breaks in DNA, and makes the damage permanent. Therefore, in oxygen absence, DNA is less vulnerable to permanent damage, leading to relative radioresistance, and the dose has to be increased substantially to induce the same cell kill. Hypoxia-inducible factor-1 (HIF-1) is an intracellular protein whose transcriptional activity is increased as a response to cellular stresses, including hypoxia (2). HIF-1 consists of a labile unit (HIF-1α) and a stable unit (HIF-1β), which heterodimerize to become transcriptionally active. In normoxia, HIF-1α undergoes proteolysis, resulting in a very low level of HIF-hetereodimers. In hypoxia, degradation of the α-unit is reduced leading to an increased level of the functional heterodimer which via binding to hypoxia response elements (HRE) induces expression of genes. Notably, HIF-1 is also regulated by other factors apart from, or in concert with molecular oxygen. HRE-elements are found in promoter or enhancement regions of various tumor-promoting families of genes, involved in anaerobic metabolism (3), angiogenesis (4), anti-apoptosis (5) and invasion and metastasizing (6). Lysyl oxidase, LOX, is upregulated in hypoxia via HIF-1 and is shown to be an independent prognostic marker also in lung cancer (7). LOX exerts its effect both locally by stimulating migration and invasive behavior, and far away from its secretory origin, preparing the metastatic niche (8). Blockade of LOX is shown experimentally to reduce the metastatic propensity of tumors. HIF-1-mediated signaling regulates virtually every step of the metastatic cascade, from migration towards blood vessels and intravasation through HIF-induced leaky endothelial cells. Further, HIF-1 inhibits anoiokis of circulating tumor cells, and hypoxic primary tumors secrete factors that permeabilize the endothelium at distant premetastatic sites (9). Every element of the stromal compartment is also influenced by hypoxia, including fibroblasts, immune, lymph and blood cells, each playing important roles in tumor progression (10) Of special interest in lung cancer, epidermal growth factor receptor (EGFR) is involved in several aspects of hypoxia. Recently, hypoxia was shown to stimulate invasion via EGFR-activation (11). EGFR is also shown to suppress specific tumor-suppressing microRNAs in response to hypoxic stress through post-translational regulation of a Dicer-regulator, AGO2 (12). A number of HIF-1-upregulated genes contribute to radioresistance, perhaps most important is the shift from glucose metabolism to a glycolytic phenotype (13). This effect increases the cell’s antioxidant capacity via accumulation of redox-buffers, thereby reducing the level of free oxygen radicals produced by radiation and thus protects the DNA from damage. Hypoxic tumors reoxygenate after radiation therapy, as a result of reduced demand because of cell death, and due to increased perfusion in tissues (14). Based on this, one would expect HIF-1α levels to decline after radiation, but the opposite is observed. This phenomenon is primarily caused by 1) increased level of free radicals, and 2) liberation of “stress granula” content, both leading to stabilization of the HIF-1α subunit (15). The initial HIF-1-increase occurs within hours of radiation. A few days thereafter, increased NO produced by infiltrating macrophages induces a second peak of HIF-1 stabilization, via NO-mediated prevention of HIF-degradation (16). Both the initial and the later increase of HIF-levels may contribute to a more aggressive phenotype and ultimately to treatment failure as cells become more prone to invade and metastasize. Several hypoxia sensitizers are in clinical trials, but so far, none are in routine use in lung cancer (17). Both HIF-1-inhbitors, as well as drugs targeting glucose metabolism should be further examined in the context of radiation therapy (13). These studies should not only be confined to fractionated therapy, but may likely also have positive impact on stereotactic ablative radiotherapy. In conclusion, tumor hypoxia is a major cause of therapy failure and tumor aggressiveness, involving a multitude of factors. As knowledge emerges, the opportunities of therapeutic interventions should be ample. References 1. Brown JM et al. Nat Rev Cancer. 2004;4:437-47. 2. Greer SN et al. EMBO J. 2012;31:2448-60. 3. Semenza GL. Semin Cancer Biol. 2009;19:12-6. 4. Jackson AL et al. Expert Opin Ther Targets. 2010;14:1047-57. 5. Lenihan CR et al. Biochem Soc Trans. 2013;41:657-63. 6. Sullivan R et al. Cancer Metastasis Rev. 2007;26:319-31. 7. Wilgus ML et al. Cancer. 2011;117:2186-91. 8. Erler JT et al. Cancer Cell. 2009;15:35-44. 9. De Bock K et al. Nat Rev Clin Oncol. 2011;8:393-404. 10. Casazza A et al. Oncogene. 2013. 11. Arsenault D et al. PLoS One. 2013;8:e55529. 12. Shen J et al. Nature. 2013;497:383-7. 13. Meijer TW et al. Clin Cancer Res. 2012;18:5585-94. 14. Rubin P et al. Clin Radiol. 1966;17:346-55. 15. Moeller BJ et al. Cancer Cell. 2004;5:429-41. 16. Li F et al. Mol Cell. 2007;26:63-74. 17. Harada H. J Radiat Res. 2011;52:545-56.

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      MS01.4 - Integration of Functional and Molecular Imaging in Radiotherapy Planning (ID 460)

      15:05 - 15:25  |  Author(s): J. McAleese, G.G. Hanna, K.J. Carson, R.L. Eakin, D.P. Stewart, L. Young, A.R. Hounsell

      • Abstract
      • Slides

      Abstract
      Radiotherapy planning and target volume delineation in lung cancer is largely based on x-ray based imaging such as CT scanning or fluoroscopy. The most widely used functional imaging technique in the diagnosis and characterisation of NSCLC is [18]Fluoro-deoxy-glucose (FDG) position emission tomography (PET). PET acquired with CT on the same scanner (PET/CT) has been shown to be superior to CT alone in the staging of NSCLC. When PET is used to select patients for curative therapy an improvement in overall survival is seen. Many clinical studies describe an impact on the use of PET for target volume delineation (TVD) in NSCLC but none describe an improvement in clinical outcomes. Several staging studies clearly demonstrated the superiority of PET/CT over CT for identification of involved mediastinal nodes. PET based TVD was also shown to improve the identification of involved mediastinal lymph nodes. In areas of atelectasis, PET can help discriminate between areas of collapsed lung and areas of tumour. A number of studies have sought to measure the impact of PET/CT based TVD on inter-observer variation or against a gold standard. When PET/CT is used for target volume delineation alone, and the baseline staging issues are removed, PET/CT reduces the undesirable impact of inter-observer variation. Considering the impact on the resultant radiotherapy plan, PET/CT based target volume delineation has been shown to reduce the dose to normal structures and this may open the possibility of dose escalation. When used in its most basic form, images from the staging PET/CT scan can be visually correlated with the radiotherapy planning (RTP) CT image to identify areas of disease for inclusion within the treatment volume. To improve the accuracy of correlation a staging PET/CT scan can be registered with the planning CT and rigid registration is recommended to undertake this. One option is to acquire a PET/CT exclusively for the purpose of RTP after a staging PET has been acquired and the patient is deemed suitable for radical radiotherapy, requiring a separate PET scan, but removing any staging or patient selection issues. Another approach is to acquire a PET/CT in the radiotherapy treatment position both for the purposes of staging and TVD and this represents a more cost effective approach. Given the nature of PET images a number of investigations have examined the use of automated methods to define the edge of the tumour. These methods include: i) Fixed thresholding based on absolute values were areas of disease above a given value are included within the target volume (e.g. SUVmax >2.5); ii) A contour based on the a percentage of the SUVmax (e.g.40% of SUVmax); iii) The use of the ratio of the SUVmax to the average SUV within a background structure to define the SUV level to generate the auto-contour; iv) More complicated analytical methods such as the watershed method. Auto contours provide consistent contours, but have difficulty dealing with normal tissue adjacent to the tumour with high SUV uptake such as the heart. There is no clear consensus on which method most closely approximates to the tumour position and tumour edge and pathological correlation has proven difficult. Another difficulty with PET based auto-contouring is the variability of SUV values due to factors other than tumour activity such patient biological factors and scanning technical factors. At present it is recommended that any PET based contouring outside of a clinical trial should be based on a visual assessment method. As PET images are acquired over a number of minutes at each table position, it has been suggested that PET could define the entire motion trajectory of a lung tumour also known as the internal target volume (ITV) of a moving lung tumour. It has been demonstrated that a 4D PET/CT generated ITV based on the 4D PET image approximates to a 4DCT ITV. A number of studies have shown sizeable differences in SUV calculation between 3D PET/CT and 4D PET/CT and it is suggested that 4DCT provides a more accurate SUV quantification. This has implications for auto-contouring and may lead to new exciting new methods of PET based TVD based on 4DCT. FDG is the most commonly used tracer owing to its high tumour specificity and the relatively long half-life of [18]F. Other fluorine based tracers have been used to quantify tumour proliferation uisng 18 deoxy-fluoro-l-thymidine (FLT) and tumour hypoxia using Fluoroazomycin Arabinoside (F-FAZA). It has been suggested that these may be used for IMRT based dose painting Work is on-going to optimise dual tracer PET acquisition. A number of recent publications have examined the utility of PET for predicting outcome after stereotactic ablative radiotherapy (SABR) and demonstrated a clear association with SUVmax and poorer outcome. This might help identify those patients who might benefit from adjuvant therapy after SABR treatment. PET may have increased accuracy in detecting recurrence following SABR and should be used in the re-staging process. There is growing evidence of a similar clinical utility for PET in the management of patients with SCLC. PET has been shown to select patients with SCLC appropriately for radical therapy, to be predictive for outcome following therapy and for TVD. In conclusion, functional imaging is an essential part of the radiotherapy planning process for both NSCLC and SCLC. For both disease sites PET is critical for baseline staging and patient selection for radical therapy. PET should be used to inform TVD in NSCLC and to guide TVD in SCLC. PET is useful for identify relapse in patients treated with radiotherapy. It may also be useful as predictor of response and for adaptive radiotherapy. On-going research is still required particularly in the era of 4D PET/CT, given the promise 4D PET/CT has for improved accuracy in quantification and volume delineation.

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Author of

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    MO23 - Radiotherapy II: Lung Toxicity, Target Definition and Quality Assurance (ID 107)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Radiation Oncology + Radiotherapy
    • Presentations: 1
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      MO23.06 - DISCUSSANT (ID 3935)

      10:55 - 11:10  |  Author(s): P. Van Houtte

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    P2.24 - Poster Session 2 - Supportive Care (ID 157)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Supportive Care
    • Presentations: 1
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      P2.24-021 - Adjuvant or Induction chemotherapy for Non Small Cell Lung Cancer treated with chemoradiotherapy: An invidual data metaanalysis of phase II trials (ID 1421)

      09:30 - 09:30  |  Author(s): P. Van Houtte

      • Abstract

      Background
      it is well known that combining chemotherapy and radiation therapy is beneficial to patients with locally advanced non small cell lung cancer compared to radiation alone or compared to a sequential approach using chemotherapy and radiation therapy. However, it is not obvious what is the best schedule. A few randomized trials assessed chemotherapy as induction before chemoradiotherapy (CT -> CTRT) versus chemotherapy as consolidation, after chemoradiotherapy (CTRT -> CT). Most of those trials are phase II trials with moderate sample sizes and were not designed to demonstrate treatment effect in terms of overall survival.

      Methods
      the study coordinators of those trials (T. Berghmans, H. Choy, P. Fournel, P. Garrido, J. Van Meerbeeck) agreed on a protocol for carrying out a meta-analysis of individual patients data and for sharing the individual patients data that were sent to the coordinating institution. Overall survival was the primary outcome, progression-free survival and toxic death occurrence were among the secondary outcomes. The treatment effect was assessed through the estimation of the hazard ratio of the survival distributions using CTRT -> CT as reference. Combined hazard ratio was obtained through Cox regression models (fixed effects) with a stratification by trial. Preplanned interactions between baseline covariates (age, sex, performance status, stage, histology) and treatment effect were assessed. Toxic death rates were analyzed per trial and odds ratios have been estimated to assess the treatment effect. Combined odds ratio was obtained by the Peto method.

      Results
      the data bases of the 5 eligible identified trials (3 with cisplatin based chemotherapy regimens, 2 with carboplatin based regimens) were shared for a total of 534 patients (CT -> CTRT 271, CTRT -> CT 263). Median ages were 60 and 61 years, stage IIIB represented 69%/70% of the patients and EOCG PS > 1 was rare (3%/2%). Median follow-up ranged from 12 months up to 66 months and rates of events from 44% to 88%. No significant difference was detected either for overall survival with an estimated HR of 0.96 (95% CI : 0.79-1.17) without heterogeneity between the 5 trials (I[2]=0) or for progression-free survival (analysis restricted to 4 out of the 5 trials), HR=0.91 (95% CI : 0.75-1.11) and absence of heterogeneity (I[2]=2%). For both outcomes, no interaction between the above specified covariates and treatment effect was found. Toxic deaths occurred overall in 3% of the patients, no detectable impact of treatment arm was found with a combined odds ratio of 0.40 and a 95 % CI overlapping 1 (0.15-1.06).

      Conclusion
      our results suggest that there is no argument in favour of one of the two therapeutic schedules when looking at overall survival or at progression free survival; however, in the absence of benefit in terms of prognosis, a more detailed evaluation of toxicity is warranted and is ongoing.