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M. Werner-Wasik

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    E02 - Radiation Toxicity (ID 2)

    • Event: WCLC 2013
    • Type: Educational Session
    • Track: Radiation Oncology + Radiotherapy
    • Presentations: 4
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      E02.1 - Cardiac Toxicity of Radiotherapy (ID 377)

      14:05 - 14:25  |  Author(s): L. Marks

      • Abstract
      • Presentation
      • Slides

      Abstract
      In patients receiving radiation for a diversity of diagnoses (e.g. Hodgkin’s Disease, breast cancer, seminoma), multiple studies demonstrate that incidental irradiation of the heart can increase the cardiac morbidity and mortality. While there is limited data in patients irradiated for lung cancer, RT-induced heart disease is likely clinically important and care should be taken to minimize incidental cardiac irradiation. Breast Cancer: Dose-response and evolution of techniques: In patients irradiated for breast cancer, there is a fairly well-defined dose/volume response for radiation-induced cardiac injury. The radiation techniques used to treat patients with breast cancer have evolved over the last several decades with a corresponding marked reduction in incidental cardiac doses (and corresponding decreased cardiac risks). For example, it has been estimated that mean heart doses were in the range of 10-15 Gy with anterior photon fields (directed to the internal mammary nodes), ≈5 Gy with tangents and medial IMN electrons, 1-2 Gy with partly-wide tangents, and <1 Gy with conformal cardiac blocking and breath hold. The cardiac implications for patients with breast cancer can be large. In some older studies the detrimental cardiac effects of radiation totally off-set the improvements in cancer-specific survival provided by RT. More modern radiation techniques clearly reduce the cardiac exposure and appear to reduce the frequency or RT-induced heart disease. However, the follow-up duration in the studies utilizing these modern techniques is not as long as are the follow-up durations in the studies using the older techniques. Thus, the long-term safety of “modern” RT can still be questioned. Timing of RT-associated heart injury in patients irradiated for breast cancer: In a classic meta-analysis (Cuzick; Recent Results Cancer Research 111:108-129, 1988; and JCO 12:452, 1994), post-mastectomy RT was associated with a reduction in overall survival at follow-up times >15 years post-RT. This observation helped fuel the traditional belief (recently being challenged) is that RT-induced cardiac injury is manifest at only extended follow-up intervals. This led our group and others to look for more short-term subclinical surrogates for RT-induced cardiac injury. Summary of our prospective study: We prospectively assessed RT-induced changes in regional myocardial perfusion in patients being treated for left-sided breast cancer using modern CT-based techniques. We noted a volume-dependent new perfusion abnormalities 6-24 months post-RT. These perfusion defects largely persist up to 6 years post-RT. The distribution of the perfusion defects follows the path of the tangential radiation field, and not the territory of a coronary artery, and thus represent microvasculature (rather than named coronary artery) injury. In patients with greater than 5% of the left ventricle within the tangential field, the incidence of new perfusion abnormalities si >50%. The functional consequences of these perfusion defects are uncertain. At short follow-up times, they are associated with a slightly increased rate of regional wall motion abnormalities. These wall motion abnormalities, however, do not always persist long-term. There are minimal, if any changes in ejection fraction noted in patients with perfusion defects. However, in patients with "severe" perfusion defects (scored by the summed rest score, SRS), there is suggestion that there might be a more meaningful reduction in ejection fraction (Marks 63:214, 2005, Lind IJROBP 55:914, 2003, Prosnitz Cancer, 110:1840, 2007). The clinical relevance of these perfusion defects remains uncertain. Perfusion defects may represent a reduction in collateral circulation making the patient more prone to develop ischemia when they (at a much later date) develop coronary artery disease. Therefore, care should be taken to minimize cardiac exposure for patients receiving left-sided RT. The use of conformal blocking (heart block), respiratory gating, and electron beam techniques are often useful to reduce cardiac exposure. Reconsideration of the timing of RT-induced cardiac injury in light of the recent analysis by Darby et al (NEJM 368:11, 2013): Darby’s report suggests that RT-induced cardiac injury in patients with breast cancer is clinically manifest relatively soon post-RT (i.e. within a few years), and that the cumulative risk increases continually up to 20 years post-RT. This suggests that the microvascular changes seen in our study (noted above) might have a clinical relevance in the short post-RT interval. Therefore, an alternative interpretation Cuzick et al (cited above) is that there is a clinically-meaningful increase in cardiac mortality in the 1-15 year post-RT interval, but that this is offset by the reduction in breast-cancer specific mortality during that time (resulting in a no net change in overall survival vs. the control group). At >15 years, the excess cardiac events exceed the cumulative anti-cancer effects, leading to the reduced overall survival noted. Lung Cancer: In patients early-stage lung cancer (N0-1), post-operative RT (PORT) is associated with an excess mortality within 0-5 years (Lancet 352:257; ’98). While the causes of the excess deaths are not noted in most studies, at least one study has noted increased cardiac deaths in this setting (Dautzenberg Cancer 86:265, ‘99). Two more-recent studies of “smaller field-PORT” (Mayer: Chest 112:954, ’97; Tradella Radio Oncol 62:11, 2002) demonstrate an improvement in overall survival with PORT, again suggesting that there is a delicate balance between RT-induced reductions in cancer-specific death and normal tissue-induced injury (Miles, IJROBP 68:1047, ‘07), totally analogous to the situation with breast cancer (Marks & Prosnitz, IJROBP 48:625, 2000). With definitive RT for lung cancer, RT-induced cardiac injury is not often reported. However, this might be under-reported as the symptoms of cardiac dysfunction (e.g. dyspnea) might be ascribed to lung disease. Better sparing of the heart during definitive RT for lung cancer is likely to improve the overall outcome. There are no clear dose/volume limits for the heart in patients with lung cancer (Gagliardi IJROBP 2010). Non-axial beams are often useful in reducing cardiac exposure, especially in patients with lower lobe tumors (Quaranta Journal Applied Clinical Medical Physics, 11:3010, 2010). Some portions of the heart might be particularly important in the genesis of RT-induced cardiac injury (e.g. pericardium, coronary arteries, left ventricle) and thus sophisticated techniques to redistribute incidental cardiac dose might be helpful. Dr Marks’s department receives grants from, or has relations with, from Elekta, Siemens, Accuray, Morphormics. Supported by NIH CA069579.

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      E02.2 - Radiation Esophagitis (ID 378)

      14:25 - 14:45  |  Author(s): J. Belderbos, C. Chen, M. Kwint, W. Uyterlinde, J. Nijkamp, M. Van Den Heuvel, J. Sonke

      • Abstract
      • Presentation
      • Slides

      Abstract
      Introduction The improved survival in locally advanced non-small cell lung cancer (NSCLC) patients treated with concurrent chemo-radiation (CCRT) comes at a price of increased esophagus toxicity. Acute esophagus toxicity (AET) occurs within 3 months after CCRT and late esophagus toxicity (LET) consists of symptoms persisting or occurring >3 months after treatment. AET is treated with dietary changes, proton pump inhibitors, analgesics, promotility agents, intravenous fluids, and/or nasogastric- or gastrostomy tube insertion. Patients who develop stenosis, perforation or fistula are categorized as severe LET (grade 3-5). Patients with stenosis are treated by dilatation. Some patients will develop a fistula, which can be treated with intraluminal stenting. However the prognosis for patients with a fistula is grim. Estimation of the probability and severity of radiation esophagitis after CCRT treatment is crucial. This allows the individual prescription of tumor doses. Several prediction models have been reported to estimate the risk of AET based on the planned dose distributions. Currently used models to predict acute esophageal toxicity (AET) in lung cancer patients after Intensity Modulated Radiotherapy (IMRT) and concurrent chemotherapy were derived from patients treated with 3D-conformal-radiotherapy (3DCRT). These models first reduce the dose-volume histograms to a single parameter like the volume of esophagus receiving more than a certain threshold dose (V~x~). In a large multi-institutional study on 1082 patients treated with 3DCRT, or IMRT concurrent with chemotherapy, the high-dose volumes were the most important predictors for radiation esophagitis [ref 1]. The V60 emerged as the best predictor for both moderate and severe esophagus toxicity. A low-risk subgroup was identified with a very low V60 of <0.07%, an intermediate-risk subgroup with a V60 of 0.07%-16.99%, and a high-risk subgroup with a V60 of ≥17%. Severe LET seriously affects the patients’ quality of life or even leads to death. For LET predicting models are lacking. With improved survival in patients treated with CCRT, it is important and feasible to analyze LET. This abstract is a summary from a series of studies conducted at NKI on esophagus toxicity in a large NSCLC patient cohort. The patients were all treated with hypofractionated radiotherapy, 66 Gy in 24 fractions, and concurrent daily low dose cisplatin. The following items were investigated: 1) Comparison of AET incidence in patients treated with 3DCRT and CCRT to sequential chemoradiation and RT only.¨ 2) Compare incidence of AET with 3DCRT to IMRT. 3) Analysis of prognostic factors for AET using IMRT. 4) Correlation of radiotherapy dose to the oesophagus wall and AET by means of post-RT 18FDG-PET scans acquired after CCRT. 5) Relations between severe LET and the clinical and dosimetric variables. Material and methods The dose-effect relation of AET (185 patients) [ref 3] and LET ≥grade 3 (171 patients) [ref 6] and dose-volume parameters of the esophagus after hypofractionated IMRT (66 Gy/24 fractions) and concurrent low dose cisplatin were investigated. The dose distributions were first converted to Normalized Total Doses to account for fractionation effects with an α/β-ratio of 10 Gy (AET) or 3 Gy (LET). Equivalent Uniform Dose (EUD) to the esophagus and the volume percentage receiving more than x Gy (Vx) were evaluated by Lyman-Kutcher-Burman model. The association between AET and severe LET (grade ≥3 RTOG/EORTC) was tested through Cox-proportional-hazards model Clinical parameters, onset and recovery times were analyzed as well. Results Acute Esophagus Toxicity -For NSCLC patients treated with 3DCRT and concurrent chemotherapy, the incidence of AET grade ≥ 2 was 27% and significantly higher compared to patients treated with sequential chemoradiation or radiotherapy only regimens [ref 2]. -The AET incidences were not significantly different between 3DCRT based and IMRT based CCRT patients. In order to illustrate the differences between 3DCRT and IMRT we show the Vx (α/β-ratio=10) in steps of 5 Gy derived from the AET study by Kwint et al, and also for 36 CCRT patients treated in the EORTC 08972 trial. From Figure 1 it can be appreciated that with IMRT the volume of esophagus receiving a dose from 5-40 Gy was significantly smaller, while at 70 Gy it was increased. Moreover, the LKB model based on the V50 was not significantly different between IMRT and 3DCRT [ref 3]. -A total of 22% NSCLC patients developed AET toxicity ≥ grade 3 after IMRT to 66 Gy in 24 fractions and concurrent daily low dose cisplatin. The V50 was identified as most accurate predictor of grade ≥ 3 AET [ref 3]. -The median time to AET grade 3 was 30 days, with a median duration of >80 days. Higher grade of AET was also associated with a lower recovery rate [ref 4]. -Post-CCRT esophageal FDG uptake on 18FDG-PET is associated with AET grade. SUV predictability of grade 2-3 AET was significantly improved by using the derived relation between RT dose and PETpost [ref 5]. Results Late Esophagus Toxicity A total of 6% patients developed LET ≥ grade 3 at a median follow-up of 33 months (95% CI 29~37) with a median overall survival of 24 months (95% CI 16~32) [ref 6]. The median onset time was 5 months (range 3~12). Patients with un-recovered AET had a significantly (p<0.001) higher risk of developing severe LET, compared to patients without AET or with a recovered AET. In the EUD; n=0.03 model, all severe LET patients had an NTD >70 Gy on the esophagus. In the EUD~n~-LKB model, the fitted values and 95% confidence intervals were TD~50=~76.1 Gy (73.2~78.6), m=0.03 (0.02~0.06) and n=0.03 (0~0.08). In the V~x~-LKB model, the fitted values and 95% CIs were Tx~50~=23.5% (16.4~46.6), m=0.44 (0.32~0.60) and x=76.7 Gy (74.7~77.5). Conclusions In routine clinical practice it is possible to provide insight in the probability and severity of esophagus toxicity for each individual lung cancer patient treated with CCRT. Both the maximum grade and the recovery rate of AET were significantly associated with severe LET. In clinical practice, NTD corrected esophagus EUD<70 Gy could be a dose constraint to minimize severe LET. AET was not changed with the use of IMRT.

      references
      1 Palma D. et al, Predicting Esophagitis after Chemoradiotherapy for Non-Small Cell Lung Cancer: An Individual Patient Data Meta-analysis. Int J Radiat Oncol Biol Phys. 2013 in press
      2 Belderbos J. et al, Acute esophageal toxicity in non-small cell lung cancer patients after high dose conformal radiotherapy. Radiother Oncol 2005;75:157-164
      3 Kwint M. et al, Acute esophagus toxicity in lung cancer patients after intensity modulated radiation therapy and concurrent chemotherapy. Int J Radiat Oncol Biol Phys. 2012 Oct 1;84(2):e223-8
      4 Uyterlinde W. et al, Prognostic parameters for acute esophagus toxicity in Intensity Modulated Radiotherapy and concurrent chemotherapy for locally advanced non-small cell lung cancer. Radiother Oncol. 2013 Jun;107(3):392-7.
      5 Nijkamp J, et al. Relating acute esophagitis to radiotherapy dose using FDG-PET in concurrent chemo-radiotherapy for locally advanced non-small cell lung cancer. Radiother Oncol 2013 Jan;106(1):118-23
      6 Chen C. et al, Severe late esophagus toxicity in NSCLC patients treated with IMRT and concurrent chemotherapy. Radiotherapy & Oncology 2013 in press
      Figure 1

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      E02.3 - Functional Biophysical Model (FUNBIPM) to Predict Radiation Lung Toxicity (ID 379)

      14:45 - 15:05  |  Author(s): F.(. Kong

      • Abstract
      • Presentation
      • Slides

      Abstract
      Treatment toxicity not only reduces quality of life, but also may be life threatening (and can be unidentified) when it is severe. Radiation induced lung toxicity (RILT) is among the most important dose limiting toxicity in the treatment of lung cancer, particularly locally advanced non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC). The current standard of RT techniques considers the whole lung as a uniform organ and uses the same dose limit for all patients with the assumption that all have a SAME sensitivity to radiation damage. However, patients with NSCLC frequently have a respiratory comorbidity such as chronic obstructive pulmonary disease (COPD) that results in heterogeneous function within different lung regions. Patients often respond remarkably differently to the same amount of radiation dose. Furthermore, the presence of the tumor itself often affects local vascular supply and ventilation, and changes function level. In this presentation, I will review the current functional imaging for lung and predictive biomarkers for RILT with an emphasis on recent advances regarding 1) ventilation/perfusion single photon emission tomography (V/Q SPECT) for treatment planning and RILT prediction, and 2) blood markers and its integration with physical and functional dosimetric factors for RILT prediction. Ultimately, we would like to generate Functional Imaging and Biophysical Model (FunBipM) to guide individualized treatment planning to minimize treatment toxicity V/Q SPECT is a commonly available technique in most hospitals to image the perfusion (Q) and ventilation (V) of the lung. It has been proposed that Q-SPECT images can be used to guide RT planning so that radiation is directed to the non-functional lung regions [1-4]. It was known to us that the Q-SPECT-guided plans produced more favorable functional dose volume histograms (DfVHs) compared to non-SPECT guided plans, with the fV20 and fV30 values reduced by an average of 13.6% ± 5.2% and 10.5% ± 5.8%, respectively [2]. We have further demonstrated that 1) NSCLC often presents with defect regions on V/Q SPECT, some of which are from tumor compression that improves with tumor shrinkage during- RT; 2) SPECT defect regions are more resistant to post-RT function reduction; 3) V/Q SPECT guided radiation therapy can reduce dose to functional lung without increasing doses to the total physical lung; 4) V/Q SPECT based DfVHs from during-RT may predict clinical significant RILT more accurately than anatomic CT lung based DVH. From treatment planning point of view, I will use example cases to demonstrate that we can avoid V/Q SPECT functional regions in pre- and during- RT to minimize damage to functional lung, particularly by the combined use of pre- and during-. V/Q SPECT adds lung ventilation mapping on top of the Q-SPECT, providing more information (including the mechanism for lung function defects and their potential for recovery). During-RT V/Q SPECT allows adaptive-RT because lung function changes globally and locally during RT, largely due to RT-induced tumor volume reduction improving the vascular supply and ventilation[5]. The combination of pre- and during- V/Q SPECT can classify the lung into different functional regions and strategize to differentially prioritize certain regions, a technique our group developed to minimize lung damage. Additionally, we can compute DfVHs from both pre- during- SPECT scans to predict post-treatment functional loss and clinically significant RILT. Patients with the same dosimetric parameters have shown very different levels of toxicity largely due to their biologically different intrinsic sensitivity to radiation damage [6]. Many studies have been conducted to understand the correlation between pro-inflammatory and pro-fibrogenic cytokines, including TGF-ß1, IL-1ß, IL-6, IL-8, and TNF-α and radiation-induced normal tissue injury [7]. TGFß1, a fibrogenic and radiation-inducible cytokine, has been known to play a key role in this process. Animal studies demonstrated significantly elevated TGFß1 mRNA and protein expression within type II pneumocytes and fibroblasts in radiation-sensitive mice after thorax radiation [8-11], which subsequently contributed to increased TGFß1 levels in circulation. The Duke University group reported that plasma TGFß1 levels at the end of radiation are correlated with the later onset of symptomatic RILT in patients treated with definitive radiation therapy [9][,][12][,][13]. Though the result was not consistently reproduced by others [14], possibly due to technique issues [15], end-of-treatment TGFβ1 correlation nevertheless has limited value. We have demonstrated that TGFß1 elevation in the middle of treatment (2-4 weeks during-treatment) relative to pre-treatment is highly correlated with late-onset grade >2 RILT in NSCLC patients [16][,][17] . Most recently, we have demonstrated that combining baseline IL-8, during-treatment TGF-ß1, and mean lung dose into a single model yielded an improved predictive ability (P<.001) for RILT compared to either variable alone [16]. The findings on baseline and during-treatment markers are more important than end-treatment markers, as they provide us an opportunity to adjust treatment accordingly. More importantly, an individual’s susceptibility to radiation normal tissue toxicity may be genetically determined, which can be measured pre-RT. Germ-line genetic variations, most often single nucleotide polymorphisms (SNPs), may play an important role in radiation damage pathogenesis. SNPs associated with molecules involved in radiation damage pathways, such as DNA double-strand break repair (ATM, XRCC1) and inflammation (TGF β1 and cytokines) have been studied for their association with clinical toxicity [18][,][19]. It was reported that SNPs in TGFβ1 and NOS3 were associated with a lower risk for radiation pneumonitis [20][,][21] whereas SNPs in ATM, IL1A, IL8, TNFa, TNFRSF1B and MIF were associated with an increased risk of radiation pneumonitis [20][,][22]. TGFβ1 rs1800470 was positively associated with RILT [21]. We also demonstrated that SNPs of TGFβ1 genes may be associated with overall risk of other organs’ toxicity, including esophagus or heart/pericardium [23]. This finding is also very important because after limiting lung toxicity to less than certain level (such as 15-17%), increased dose to the most resistant tumors may increase toxicity of other organs. This is complicated but should be taken into consideration. In summary, we may generate a FunBipM through the combination of pre- and during-RT V/Q functional dosimetric parameters and blood biomarker data to predict the risk of lung toxicity for each individual patient: i.e. using a FunBipM that integrates biologic markers into the existing dosimetry-based model. By identifying high-risk patients, adjusting lung dose limit according to the threshold of tolerance, and applying the FunBipM to optimize radiation planning for dose and dose arrangement, we may anticipate a significant reduction of the incidence of toxicity without compromised tumor control.1. Seppenwoolde Y, Engelsman M, De Jaeger K, et al. Optimizing radiation treatment plans for lung cancer using lung perfusion information. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology. May 2002;63(2):165-177.2. McGuire SM, Zhou S, Marks LB, Dewhirst M, Yin FF, Das SK. A methodology for using SPECT to reduce intensity-modulated radiation therapy (IMRT) dose to functioning lung. International journal of radiation oncology, biology, physics. Dec 1 2006;66(5):1543-1552.3. Lavrenkov K, Christian JA, Partridge M, et al. A potential to reduce pulmonary toxicity: the use of perfusion SPECT with IMRT for functional lung avoidance in radiotherapy of non-small cell lung cancer. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology. May 2007;83(2):156-162.4. Lavrenkov K, Singh S, Christian JA, et al. Effective avoidance of a functional spect-perfused lung using intensity modulated radiotherapy (IMRT) for non-small cell lung cancer (NSCLC): an update of a planning study. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology. Jun 2009;91(3):349-352.5. Yuan S, Frey KA, Gross M, Hayman J, Arenberg D, Cai X. Changes in global function and regional ventilation and perfusion on SPECT during the course of radiotherapy in patients with non-small-cell lung cancer. International journal of radiation oncology, biology, physics. 2012;82(4):e631-638.6. Kong FM, Ao X, Wang L, Lawrence TS. The use of blood biomarkers to predict radiation lung toxicity: a potential strategy to individualize thoracic radiation therapy. Cancer control : journal of the Moffitt Cancer Center. Apr 2008;15(2):140-150.7. Kong FM, Ten Haken R, Eisbruch A, Lawrence TS. Non-small cell lung cancer therapy-related pulmonary toxicity: an update on radiation pneumonitis and fibrosis. Seminars in oncology. Apr 2005;32(2 Suppl 3):S42-54.8. Yi ES, Bedoya A, Lee H, et al. Radiation-induced lung injury in vivo: expression of transforming growth factor-beta precedes fibrosis. Inflammation. Aug 1996;20(4):339-352.9. Anscher MS, Kong FM, Marks LB, Bentel GC, Jirtle RL. Changes in plasma transforming growth factor beta during radiotherapy and the risk of symptomatic radiation-induced pneumonitis. International journal of radiation oncology, biology, physics. Jan 15 1997;37(2):253-258.10. Bai YH, Wang DW, Cui XM, et al. Expression of transforming growth factor beta in radiation interstitial pneumonitis. Journal of environmental pathology, toxicology and oncology : official organ of the International Society for Environmental Toxicology and Cancer. 1997;16(1):15-20.11. Rube CE, Uthe D, Schmid KW, et al. Dose-dependent induction of transforming growth factor beta (TGF-beta) in the lung tissue of fibrosis-prone mice after thoracic irradiation. International journal of radiation oncology, biology, physics. Jul 1 2000;47(4):1033-1042.12. Vujaskovic Z, Marks LB, Anscher MS. The physical parameters and molecular events associated with radiation-induced lung toxicity. Seminars in radiation oncology. Oct 2000;10(4):296-307.13. Kong FM, Anscher MS, Sporn TA, et al. Loss of heterozygosity at the mannose 6-phosphate insulin-like growth factor 2 receptor (M6P/IGF2R) locus predisposes patients to radiation-induced lung injury. International journal of radiation oncology, biology, physics. Jan 1 2001;49(1):35-41.14. De Jaeger K, Seppenwoolde Y, Kampinga HH, Boersma LJ, Belderbos JS, Lebesque JV. Significance of plasma transforming growth factor-beta levels in radiotherapy for non-small-cell lung cancer. International journal of radiation oncology, biology, physics. Apr 1 2004;58(5):1378-1387.15. Zhao L, Wang L, Ji W, Lei M, Yang W, Kong FM. The influence of the blood handling process on the measurement of circulating TGF-beta1. Eur Cytokine Netw. Mar 1 2012;23(1):1-6.16. Stenmark M, Cai X, Shedden K, et al. Combining Physical and Biologic Parameters to Predict Radiation-Induced Lung Toxicity in Patients With Non-Small-Cell Lung Cancer Treated With Definitive Radiotherapy. International journal of radiation oncology, biology, physics. In press.17. Zhao L, Wang L, Ji W, et al. Elevation of plasma TGF-beta1 during radiation therapy predicts radiation-induced lung toxicity in patients with non-small-cell lung cancer: a combined analysis from Beijing and Michigan. Int J Radiat Oncol Biol Phys. Aug 1 2009;74(5):1385-1390.18. Damaraju S, Murray D, Dufour J, et al. Association of DNA repair and steroid metabolism gene polymorphisms with clinical late toxicity in patients treated with conformal radiotherapy for prostate cancer. Clinical cancer research : an official journal of the American Association for Cancer Research. Apr 15 2006;12(8):2545-2554.19. Hart JP, Broadwater G, Rabbani Z, et al. Cytokine profiling for prediction of symptomatic radiation-induced lung injury. International journal of radiation oncology, biology, physics. Dec 1 2005;63(5):1448-1454.20. Hildebrandt MA, Komaki R, Liao Z, et al. Genetic variants in inflammation-related genes are associated with radiation-induced toxicity following treatment for non-small cell lung cancer. PLoS One. 2010;5(8):e12402.21. Yuan X, Liao Z, Liu Z, et al. Single nucleotide polymorphism at rs1982073:T869C of the TGFbeta 1 gene is associated with the risk of radiation pneumonitis in patients with non-small-cell lung cancer treated with definitive radiotherapy. J Clin Oncol. Jul 10 2009;27(20):3370-3378.22. Zhang L, Yang M, Bi N, et al. ATM polymorphisms are associated with risk of radiation-induced pneumonitis. Int J Radiat Oncol Biol Phys. Aug 1 2010;77(5):1360-1368.23. Xie C, Yuan S, Ellingrod V, Hayman J, Arenberg D, Curtis JL. The Value of Single Nucleotide Polymorphisms in TGFβ1, TPA and ACE in Survival Prediction in Patients with Non-small Cell Lung Cancer. International journal of radiation oncology, biology, physics. 2010;78(3 suppl):199S - 200S.

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      E02.4 - Neurotoxicity of Cranial Irradiation (ID 380)

      15:05 - 15:25  |  Author(s): A. Sun

      • Abstract
      • Presentation
      • Slides

      Abstract
      Overview of acute and late toxicities of brain irradiation Acute side effects of brain irradiation (BI) include common effects such as scalp erythema, alopecia, and fatigue and less common effects such as otitis externa, impaired sense of taste, nausea, and headache. Early delayed and late side effects from BI may include hyperpigmentation of the scalp, alopecia, hearing loss, behavioral changes, somnolence syndrome, radiation necrosis and neurocognitive decline. Brain Metastases (BM) often have a devastating impact on neurocognitive function (NCF). BI has been shown to treat, prevent or delay the incidence of BM in lung cancer. However, it can also cause toxicity resulting in a decline in NCF. To date there is limited data available regarding the effects of BI on NCF in patients with lung cancer. This is due to the lack of intensive NCF testing in lung cancer trials. Mechanisms of injury The pathophysiology of late radiotherapy injury is a dynamic and complex interaction between the vasculature and the parenchyma. The vascular hypothesis of radiation-induced injury describes a process of accelerated atherosclerosis causing vascular insufficiency, resulting in a picture similar to small vessel disease seen with vascular dementia. For this reason there is interest in studying vascular dementia treatments to prevent or reduce radiation-induced NCF decline. Glutamate is the principle excitatory amino acid neurotransmitter in cortical and hippocampal neurons. One of the receptors activated by glutamate is the N-methyl-D-aspartate (NMDA) receptor, which is involved in learning and memory. Ischemia can induce excessive NMDA stimulation and lead to excitotoxicity, suggesting that agents that block pathologic stimulation of NMDA receptors may protect against further damage in patients with vascular dementia. Memantine, an NMDA receptor antagonist, has been shown to be neuroprotective in preclinical models. Additionally, two placebo-controlled phase III trials found memantine to be well-tolerated and effective in treatment for vascular dementia. On these basis, RTOG launched a placebo-controlled, double-blind, randomized trial to evaluate the potential protective effect of memantine on NCF in patients receiving whole brain radiation (WBRT). The results of this study (RTOG 0614) were recently reported. Predisposing factors It is the therapeutic ratio of benefits vs. risks that helps determine the advisability of a treatment such as BI. Clinical trials of prophylactic cranial irradiation (PCI) can enable us to develop strategies that can potentially increase the benefits and decrease the risks. Potential strategies that can increase the benefits of BI may require better ways of identifying a subgroup of patients with the highest risk of developing BM such as those with small cell lung cancer (SCLC), adenocarcinoma, young age, high volume of disease and predictive markers. These are the patients most likely to benefit from PCI. In order to develop strategies to decrease the risks, we must identify and understand those risks. Identifying a subgroup of patients with the highest risk of developing NCF toxicities, such as older age or other patient factors such as hypertension and diabetes, may also improve the therapeutic ratio. Dose volume determinants Due to the concerns with NCF with WBRT, stereotactic radiosurgery (SRS) approaches are being actively studied. Combined therapy (SRS+WBRT) for BM are favored based on Phase III findings that brain control with combined therapy is significantly better than with SRS alone or WBRT alone. On the other hand, a phase III study found that the risk of neurocognitive deficit is doubled with the addition of WBRT to SRS. The published data demonstrate continued evolution of clinical trials and different management strategies are currently being evaluated in prospective clinical trials to minimize the likelihood of cognitive decline following BI. To reduce cognitive injury of conventional WBRT, several groups are exploring modified WBRT approaches, such as hippocampal-avoidance WBRT (HA-WBRT). In this approach, complex planning techniques are used to reduce dose to bilateral hippocampal structures while treating the rest of the brain. Hippocampal-dependent functions of learning, memory, and spatial information processing seem to be preferentially affected by RT. It is argued that since <5% of BM occur within 5 mm of the hippocampus, reducing dose to the hippocampus is safe and feasible. The feasibility of this approach has been studied prospectively in a multi-institutional setting by the RTOG study 0933. Clinical features and diagnosis Publications on radiation-induced neurotoxicity have used different assessment methods, time to assessment, and definition of impairment, thus making it difficult to accurately assess the rate and magnitude of the NCF decline that can be expected. There is a paucity of data on neurocognitive impairment after BI, which has previously been assessed using various different neuropsychological tests, as well as different definitions of neurocognitive impairment. It must be remembered that NCF is affected by a number of factors (i.e. BM volume, disease progression (intra and/or extra-cranial progression), chemotherapy, hormonotherapy, surgery, radiation, prior neurologic disease, medications, paraneoplastic effects, etc.) which should be considered when evaluating of the actual neurocognitive effect of treatments such as BI. In addition, a challenge that plagues most studies in patients with advanced cancers, is the decline in compliance with NCF testing over time. Nevertheless, many studies have been completed and will be presented. Prevention and treatment. Because treatment of NCF decline after radiation is limited, treatments ideally would be developed to prevent the detrimental cognitive effects of BI as discussed above. Determining the impact of BI on NCF would provide support for therapeutic decision making for an individual patient, for which we need to use sensitive cognitive assessments to elucidate the incidence, time course, intensity, domains of NCF changes following BI and their actual impact on patient quality of life (QOL). Selected References Sun A, et al. Phase III trial of prophylactic cranial irradiation compared with observation in patients with locally advanced non-small-cell lung cancer: Neurocognitive and quality-of-life analysis. J Clin Oncol 2011;29:279-286. Chang EL, et al. Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: A randomised controlled trial. Lancet Oncol 2009;10:1037-1044. Wolfson AH, et al. Primary analysis of a phase III randomized trial radiation therapy oncology group (RTOG) 0212: Impact of different total doses and schedules of prophylactic cranial irradiation on chronic neurotoxicity and quality of life for patients with LD-SCLC. IJROBP 2011;81:77-84.

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    HOD1 - Mondays Highlights of the Day - Radiotherapy, Radiology and Surgery (ID 226)

    • Event: WCLC 2013
    • Type: Highlight of the Day Session
    • Track: Radiation Oncology + Radiotherapy
    • Presentations: 1
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      HOD1.1 - Radiotherapy (ID 4042)

      07:00 - 07:30  |  Author(s): M. Werner-Wasik

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    MO17 - Radiotherapy I: Stereotactic Ablative Body Radiotherapy (ID 106)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Radiation Oncology + Radiotherapy
    • Presentations: 1
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      MO17.05 - Recurrence, Survival, and Toxicity after Stereotactic Lung Radiotherapy (SBRT) for Central versus Peripheral Stage I Non-Small Cell Lung Cancer (NSCLC): Results from an International Collaborative Research Group (ID 3436)

      16:35 - 16:40  |  Author(s): M. Werner-Wasik

      • Abstract
      • Presentation
      • Slides

      Background
      SBRT is an accepted safe and effective treatment modality for peripheral (P) stage I NSCLC tumors. Concern of excessive toxicity, however, limits its use for central (C) tumors. This study evaluates outcomes and toxicities after cone-beam CT (CBCT) image-guided SBRT for central vs. peripheral NSCLC.

      Methods
      959 lung tumors were treated with lung SBRT from 1998-2012 at five international centers participating in the Elekta Collaborative Lung Research Group; 98% underwent online CBCT IGRT. 100 cases were classified as Central (C) and 869 Peripheral (P), defined as ≤2cm vs. >2cm from the proximal bronchial tree, respectively. Staging included chest CT and routine chemistry for all; 93% had PET staging (mean time PET to SBRT 6.4 weeks); 6% had mediastinal sampling (mediastinoscopy or endobronchial ultrasound). 61% had tumor biopsy (84% C vs. 59% P, p<0.001). 89% were medically inoperable with mean baseline FEV1 of 1.6L (63% of predicted) and mean baseline DLCO of 12.1 ml/min/mmHg (56% of predicted). Mean age was 74y (42-93) with a large range in ECOG performance status (27%; 47%; 23%; 26% for 0-3, respectively). Clinical stage was T1aN0 44%, T1bN0 30%, T2aN0 23%, T2bN0 32%. Mean tumor maximum dimension was 2.5cm (range 0.5-8.5cm); C tumors were larger (mean 3.lcm vs. 2.4 cm, p<0.001). Mean SBRT prescription dose was 51.5±6.4 Gy, with mean dose per fraction of 14.5±4.0 Gy in 3.9±1.5 fractions. Mean biological equivalent dose (BED) was 126.6±26.6 Gy, higher for P vs. C tumors (129.2 vs. 104.0 Gy, p<0.001. Chemotherapy was administered more for C (9%) than P tumors (2%), p<0.001. Groups were compared with t-test & chi-square. Competing risks analyses were used, accounting for the competing risk of death.

      Results
      Mean follow-up for all cases was 1.8y (0.1-7.7y; mean potential follow-up 3.4y), similar for C&P. C tumors had higher Local Failure (LF) (3y-LF 16.2%C vs. 5.9%P; 5y-LF 20.4%C vs. 8.3%P, p<0.001), similar regional nodal recurrences (RR) (3y-RR 12%C vs.12%P, p=0.69) and distant metastases (DM) (3y-DM 19%C vs 20%P, p=0.75), lower cause-specific survival (CSS) (3yr-CSS 75%C vs. 88%P, p<0.001), but similar overall survival (OS) (3y-OS 50%C vs. 51%P, p=0.70). Grade > 2 pneumonitis was higher for C tumors (8%C vs. 1%P, p<0.001). Incidence of grade 3 pneumonitis, chest wall pain/myositis, rib fracture, and skin dermatitis were rare (0.8%, 0.5%, 0.4%, 0.6% respectively for all) with no differences between C&P. No grade 4 toxicities were noted, though 2 cases (1C & 1P) of fatal pneumonitis were potentially attributable to SBRT. On multivariate analysis, BED (HR:0.975, p<0.001) predicted CSS, and both BED (HR:0.978, p=0.002) and baseline SUVmax (HR:1.04, p=0.001) predicted LF. Weeks from PET-staging until SBRT (HR:1.25, p=0.004) and the percent of lungs receiving >20 Gy (HR:1.063, p=0.001) were the strongest independent predictors of OS.

      Conclusion
      In this large data set, pneumonitis was higher for central tumors, but both central & peripheral SBRT were safe with similar overall and cause-specific survival. LF was higher for central tumors, which were larger, had higher baseline SUVmax, and received lower dose. Results of the ongoing RTOG 0813 dose-finding study for central tumors are awaited.

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    P2.12 - Poster Session 2 - NSCLC Early Stage (ID 205)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P2.12-015 - Investigation of the FDG PET-derived Total Glycolytic Activity (TGA) as Prognostic Tool in Patients with Early Stage Resected Non-Small Cell Lung Cancer (ID 1989)

      09:30 - 09:30  |  Author(s): M. Werner-Wasik

      • Abstract

      Background
      While the maximum standardized uptake values (SUV max) on the preoperative positron emission tomography (FDG PET-CT) have been associated with tumor recurrence in patients (pts) with resected early stage non-small cell lung cancer (ES-NSCLC), we investigated the prognostic role of tumor volume, using the Total Glycolytic Activity (TGA).

      Methods
      Pts with resected ES- NSCLC and single primary tumors without intrathoracic dissemination, staged with FDG PET-CT scans from 2006-2011 were included. Anonymized images of tumors were contoured with a commercially available semi-automatic gradient-based tool in order to derive the Metabolic Tumor Volume (MTV) and the SUV max/mean. The TGA (a product of the MTV and the SUV mean), was calculated. Patient-related, PET-derived and pathologic tumor characteristics were evaluated in univariable Cox proportional hazards models for association with Disease Free Survival, DFS. Factors significantly associated with DFS were included in multivariable models with either TGA or SUV max. Akaike Information Criterion (AIC) was used to compare the fit of the models. LogTGA was used due to a skewed distribution.

      Results
      170 pts with 121 PET scans were initially identified; 76 images were uploadable and 13 pts were excluded (1, small-cell lung cancer; 12, biopsy), leaving 63 analyzable pts. Median age was 69 (50-87) and 46% were males. Average time from FDG PET to surgery was 39 days (0-152). There were 55 (87 %) lobectomies/pneumonectomies and 8 (13%) wedge resections. Tumor histology was: 42 (66.7%) adenocarcinoma; 13 (20.6%) squamous cell carcinoma (SCCa); 4 (6.3%) adenosquamous (ASCa); 4 (6.3%) large cell (LCCa). Median tumor largest dimension was 2 cm (0.7-10.0); 12 (21.1%) tumors had lymphovascular invasion; 10 (18.5%) were node-positive (10 [17.2%] N1 and 2 [3.4%] N2); 3 pts had positive resection margin. Adjuvant treatment was given to 15 (24%) pts (13, chemotherapy; 4, radiation therapy). Median follow-up (FU) time was 32.2 months (mo) (0-83.8). Eighteen pts experienced disease progression and the first failure sites were: local (2); regional (4) and distant (16). Mean time to recurrence was 23.8 mo (median time, not reached) and 14 pts died. Median survival time (ST) was not reached; mean ST was 46.3 mo. Median MTV, median SUV max, median SUV mean and median TGA were as follows: 3.48 cc (range: 0.72-110.43); 6.25 (1.24-29.04); 3.56 (0.84-12.55); 10.22 (1.68-723.66). In univariable analysis, ASCa and LCCa were significantly (p = 0.011) associated with recurrence, compared to SCCa, and increasing logTGA showed a trend (p=0.12) for worse DFS. In multivariable analysis, log TGA and SUV max failed to reach statistical significance (p = 0.167 and 0.445, respectively); however, the log TGA model was found to fit the data slightly better than the SUV max model (AIC = 131.2 vs. 132.5, respectively). In the log TGA model, pts with ASCa and LCCa were 7.6 times more likely to have recurrence than those with SCCa (p = 0.04).

      Conclusion
      ASCa and LCCa histologies were associated with worse DFS . Log TGA may be a more informative measure for disease free survival than SUV max; however, further study of a larger size is needed.