CT-APPEARANCE OF LUNG RADIATION INJURY AFTER STEREO-TACTIC BODY RADIATION THERAPY: DIFFERENCES BETWEEN PATIENTS WITH AND WITHOUT PULMONARY EMPHYSEMA

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4 oral PREDICTIVE MODELS FOR DYSPHAGIA AFTER (CHEMO)RADIATION IN HEAD AND NECK CANCER: A MULTICENTER PROSPECTIVE COHORT STUDY M. Christianen", C. Schilstra", H. P. Bijll, I. Beetz ' , O. Chouvalova". R. Steenbakkers", F. Burlaqe ", P. Doornaert", D. Rietveld 2 , C. R. t.eemans", R. Rinkel 3 , B. F. van der taan", I. Verdonck-de t.eeuw", H. Langendijk l 1 UNIVERSITY MEDICAL CENTER GRONINGEN / UNIVERSITY OF GRONINGEN, Radiation Oncology, Groningen, Netherlands 2 VU UNIVERSITY MEDICAL CENTER, Radiation Oncology, Amsterdam, Netherlands 3 VU UNIVERSITY MEDICAL CENTER, Otolaryngology/Head and Neck Surgery, Amsterdam, Netherlands 4 UNIVERSITY MEDICAL CENTER GRONINGEN / UNIVERSITY OF GRONINGEN,Otolaryngology/Head and Neck Surgery, Groningen, Netherlands

Purpose: Results of clinical studies suggest that dose distributions in the pharyngeal muscles and laryngeal structures are significantly associated with the probability of dysphagia after curative (chemo) radiation ((CH)RT) in head and neck cancer (HNC) patients. The purpose of this multicenter prospective cohort study was to identify which DVH-parameters and other determinants are most important to predict dysphagia at 12, 18 and 24 months after (CH)RT. Materials: The study population was composed of 369 consecutive patients with HNC treated with curative (CH)RT. The primary endpoint was grade 2 or more dysphagia according to the RTOG/EORTC late radiation morbidity scoring criteria at 12 (SWALM12), 18 (SWALM18), and 24 months (SWALM24) after (CH)RT. All organs at risk potentially involved in swallowing were delineated on the planning CT-scan according to strict guidelines, including the pharyngeal constrictor muscle (PCM) superior, medius and inferior; cricopharyngeal muscle; esophagus inlet muscle; (supra)glottic area; soft palate; parotid and submandibular salivary glands. Patients with grade 2 or more dysphagia at baseline were excluded. To select the most predictive variables for dysphagia, a multivariate logistic regression model with bootstrapping was used. Results: At 12 months after (CH)RT 275 patients were available for analysis, with a prevalence of 15.60/0 for SWALM12. A model with the mean dose to the PCM superior and to the PCM medius was most predictive for dysphagia. The odds ratios (ORs) were 1.05 (95 %CI: 1.02 1.08) (for each Gy increase in dose) and 1.04 (95 %CI: 1.00 1.09) (for each Gy increase in dose), respectively. Model performance was good with an area under the curve (AUC) of 0.79.For the analysis of SWALM18, 207 patients were available, with a prevalence of 13% of SWALM18. Again, a model based on the mean dose to the PCM superior and to the PCM medius was most predictive for dysphagia. The ORs were 1.06 (95%CI: 1.02 1.11) (for each Gy increase in dose) and 1.07 (95% C I : 1.01 1.14) (for each Gy increase in dose), respectively. Model performance was good with an AUC of 0.85.The prevalence among the 142 patients available for SWALM24 analysis was 11.9%. A model with only one determinant was most predictive: the mean dose to the PCM superior with an OR of 1.10 (95%CI: 1.04 1.15) (for each Gy increase in dose). Model performance was good with an AUC of 0.83. Conclusions: This large prospective cohort study revealed that grade 2-4 dysphagia 12 and 18 months after curative (CH)RT is best predicted by a model consisting of the mean dose to the PCM superior and the PCM medius. For 24 months a model with the mean dose to the PCM superior was most predictive. The effect of the mean dose to the PCM superior on dysphagia increases with time.These models provide important information for optimizing dose distributions using swallowing sparing IMRT. 5 oral A NOVEL DOSE-RESPONSE MODEL FOR XEROSTOMIA ALLOWING FOR REGIONAL VARIATIONS IN RADIO-SENSITIVITY OF THE PAROTID F. Buettner", A. Miah 2 , S. GUllifordl, K. Harrlnqtorr", S. Webb l, M. Partridqe", C. Nutting 2 1 THE INSTITUTE OF CANCER RESEARCH AND ROYAL MARSDEN HOSPITAL NHS FOUNDATION TRUST, Joint Department of Physics, London, United Kingdom 2 THE ROYAL MARSDEN NHS FOUNDATION TRUST, Department of Clinical Oncology, London, United Kingdom

Purpose: Radiation-induced xerostomia is commonly modeled based on the mean dose to salivary glands. Current NTCP models treat the parotids as homogeneous organs and do not reflect intra-glandular differences in tissuefunction. We generated an NTCP model of xerostomia reflecting the anatomy of the salivary glands and taking the spatial distribution of the dose into account and quantified the influence of potential regional variations in radiosensitivity on outcome. Materials: We sub-divided the parotids into deep and superficial lobes and quantified the shape of the dose distribution within the lobes using 3D invariant statistical moments. Furthermore, we considered the volume of the lobes, the mean dose to the submandibular glands and surgical removal of the ipsi-

lateral submandibular gland as potential predictors. We used a Bayesian variable selection algorithm to find the best subset of the potential predictors for multivariate logistic regression by calculating the probabilities of being the best model for all potential models. We used leave-one-out cross-validation (LOOCV) and calculated the area under the ROC curve (AUC) which quantifies the ability of the dose-response models to predict xerostomia 2: grade 2 (LENTSOM) after 12 months. This methodology was applied to 63 patients treated with either IMRT or conventional radiotherapy who participated in the PARSPORT trial (CRUKl03/005). Results: Taking deep and superficial lobes into account separately resulted in equal or better mean dose models than standard mean dose models. Including morphological information yielded a further increase of AUC. For IMRT patients only, the standard mean dose model had an AUC of 0.63. A model based on the mean dose to the combined superficial lobes resulted in an AUC of 0.70. The best morphological model had an AUC of 0.88 and was based on the spread of the dose to the medial and inferior part of the deep lobe (m011d), the skewness of the dose in cranio-caudal direction in the superficiallobe (m003s) and surgical removal of the ipsi-Iateral submandibular gland. For conventional patients, both mean dose models had AUCs of 0.51. The best morphological model with an AUC of 0.74 was based on the overall skewness of the deep lobe (m 111d), mo 11s and the mean dose to the submandibular gland. A joint model for all patients resulted in AUCs of 0.71 and 0.73 for conventional mean dose models and a model based on the mean dose to the combined superficial lobes, respectively. The best morphological model had an AUC of 0.80 and was based on mean dose to the superficial lobe, mO11d, m 111s. Thus, the dose to the superficial lobes, the relative concentration of the dose to the medial and inferior part (m011) and information on the submandibular gland were specifically important predictors. Conclusions: By including anatomical and morphological information we were able to identify NTCP models with a considerably higher predictive power than standard mean-dose models. 6 oral CT-APPEARANCE OF LUNG RADIATION INJURY AFTER STEREOTACTIC BODY RADIATION THERAPY: DIFFERENCES BETWEEN PATIENTS WITH AND WITHOUT PULMONARY EMPHYSEMA F. Casamasslma", S. Masciullo", C. Menlchelli", I. Bonucci", L. Masi l, R. Doro l 1 U.O.RADIOBIOLOGIA CLiNICA UNIVERSITA 01 FIRENZE, Firenze, Italy

Purpose: High-dose irradiation is limited by adverse effects on normal tissues, much more susceptible to dose of fraction than to total dose. However, the concept of SBRT implies hypofractionation regime. Healthy lung tissue is strongly susceptible as in the interstitial as in the alveolar structures. The lung, moreover, is a parallel organ in which is essential to reduce the treated volume. This goal can be achieved using highly conformational techniques, in order to reduce the normal tissue volume and the dose to avoid clinical manifestation. It is well-known that there is a different radiosensitivity in different lung sub-regions, and also that pulmonary emphysema, because of little normal lung tissue present around the tumor mostly surrounded by air, can represent a safeguard for the lung. In this study we evaluate CT appearance of the lung after SBRT in the normal tissue surrounding the tumor, in respect to tumor localization (upper vs lower lobe), pulmonary emphysema, PTV, total dose and dose/fraction. Materials: 131 patients with primary (T1 ;2NO) or metastatic lung cancer with 202 total lesions were treated by image-guided stereotactic radiotherapy. The mean PTV was 44,5 cc. Treatment was delivered in 1-4 fractions, with dose/fractions between 8 and 30 Gy and total dose between 20 and 36 Gy, employing a dynamic conformal arc technique with coplanar and no-coplanar arcs and 6 MV Linac (Elekta Synergy) equipped with dynamic mMLC and Cone-Beam CT. The dose was prescribed to the isocenter, requiring the PTV to be covered by the 90% of the prescription dose. Pulmonary emphysema was diagnosed in the 48% of the patients (considering as emphysematous those patients with residual volume lower than 20% of the normal value). Results: For the whole 174 lesions we evaluated the results using the modified RECIST criteria. The rate of complete response was 34%, for the partial response was 29% (26% SD, 11% PD). CT-appearance of radiation injury of the lung was classified in five patterns for acute radiation pneumonitis (within six months after SBRT) and in three patterns for radiation fibrosis (later than six months). Acute CT-appearance: Diffuse consolidation, Patchy and ground-glass opacities (GGO), Diffuse GGO, Patchy GGO, No evidence of increasing density. Late CT-appearance: Modified conventional pattern, Mass-like pattern, Scar-like pattern. These CT-appearances Wf!re apart evaluated in the subgroup of the emphisematous patients, in which there were less severe modifications, with a higher prevalence of no evidence and scar like patterns. Considering the tumor localization, the prevalence of radiation pneumonitis was higher in the lower lobe than in the upper one. Conclusions: SBRT can be performed effectively and safely in the whole patients (clinical toxicity no higher than Grade 1 CTCAE) and in particular in the subgroup of emphysematous patients, in which the CT-appearance of radiation injury is less severe than non emphysematous patients. These patients are candidates for SBRT for lung cancer, also because of their inoperability for low pulmonary function. Low toxicity in these patients can be explained because normal lung tissue seldom exists around the tumor in patients with

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pulmonary emphysema and more perfusion defects are observed, so that the tumor is mostly surrounded by air, reducing in this way the NTCP. V20 in patients with pulmonary emphysema is lower than in patients without emphysema as a result of excessive expansion of the lungs by the increase in residual volume.

Integrated dosimetric tools for prediction of normal tissue effects

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8 speaker VOLUME EFFECTS FOR LATE ADVERSE EFFECTS AFTER ADJUVANT BREAST RADIOTHERAPY J. R. Yarnold 1 , R. Owen", J. Haviland" 1 THE ROYAL MARSDEN NHS FOUNDATION TRUST, Academic Radiotherapy, Sutton, United Kingdom 2 GLOUCESTERSHIRE ONCOLOGY CENTRE, Clinical Oncology, Cheltenham, United Kingdom 3 INSTITUTE OF CANCER RESEARCH, Clinical Trials and Statistics Unit (ICR-CTSU), Section of Clinical Trials, Sutton, United Kingdom

7 speaker CLINICAL-DOSIMETRIC PREDICTIVE MODELLING INDUCED TOXICITY: THE RECTUM PARADIGM R. Valdagni 1

OF

RADIO-

1 FONDAZIONE IRCCS ISTITUTO NAZIONALE DEI TUMORI, Directorate, Prostate Program, Milan, Italy

Scientific

Systems that enable scientific prediction of a range of clinical outcomes for a single patient are of increasing interest in the medical community, and are now becoming a reality in several fields of oncology. Although numerous tools are available in radiation oncology for predicting relevant clinical endpoints, very few integrated clinical-dosimetric predictive models are available for calculating the individual risk of radio-induced toxicity. In the past 10 years, many studies have focused on evaluating the dosevolume relationship and identifying factors that influence radio-toxicity. Of interest in radiotherapy practice, the Quantec task-force recently published an extensive review of existing information regarding dose constraints and on normal tissue complication probability parameterization for many organs-at-risk. Pre-treatment estimation of the risk of toxicity has been, and remains, essentially relegated to the "heavyweight" variables (e.g., dosevolume parameters), but the present state of the art lacks an integrated approach that could include clinical (and possibly genetic) factors. The use of dosimetric constraints is of essential value in radiotherapy planning and optimization, but its weakness is an inability to predict toxicity in individual patients. If we want to move from the concept of "group prediction" to achieve "individualized prediction", it is necessary to pay more attention to clinical risk factors related to the patient's previous medical history and co-morbidities, and possible concomitant pharmacological, biological, and genetic modifiers of radio-induced toxicities, in addition to the dosimetric information. All relevant information that could potentially influence adverse events should be included within reliable predictive models. It is worth noting that non-dosimetric risk factors can playa significant role in causing radiation toxicities, particularly when the influence of dosimetric parameters is greatly minimized with the strict application of dose constraints, which are widely practiced in current radiotherapy that employs IMRT and IGRT techniques. Personalized medicine is a new approach to patient care that aims at acquiring a deeper knowledge of each patient's characteristics to better understand the synergistic effect of different factors with respect to the studied end point. This presentation is focused on the "rectum paradigm"; Le., the experience gained during studies on late rectal toxicities, with peculiar attention to the Dutch multicenter Phase III trial (randomizing between 68 and 78 Gy) and to the Italian trials AIROPROS 0101 and AIROPROS 0102. The evolution of studies on rectal toxicity appears to have established a paradigm in this field because the thread that has emerged among published results could serve as a guide for future studies on other organs-at-risk. In analyzing the literature regarding late rectal radio-induced toxicity, it becomes evident that in the initial phase, the systematic and prospective recording of reliable dosevolume and toxicity information led to the identification of dosevolume constraints and to the development of probability models for normal tissue complications that could be applied in treatment planning optimization. In the later phase, the systematic use of these dosevolume constraints enabled minimization of the influence of dosimetric variables, thereby revealing significant clinical/pharmacological risk factors. Nonetheless, it is now evident that despite the inclusion of dosimetric and clinical parameters in the models, individual radio-susceptibility still plays a significant role. A further step has recently been accomplished: the analysis of individual dosevolume information coupled with a single patient's genetic makeup has possibly led to an initial advance regarding our knowledge of the impact of gene expression profiling on patients' radiosensitivity and radioresistance. The results of these investigations are important indicators of how we could improve predictive modelling of rectal bleeding, as well as other acute and late rectal symptoms such as fecal incontinence and increased stool frequency. Furthermore, user-friendly clinical-dosimetric tools for clinicians (such as nomograms) and more complex systems (such as artificial neural network models) are under development with the aim of improving the prediction of acute and late radio-induced rectal syndrome after conformal irradiation for prostate cancer. It is highly probable that in the future easy-to-use tools for the prediction of radioinduced toxicity in the single patient also including biomolecular and genetic information will be developed.

Purpose: Stratification of dose intensity in partial breast radiotherapy and whole breast radiotherapy using synchronous boost dose techniques requires more precise estimates of volume effects for dose-limiting late normal tissue responses. Materials: Gradients of the dose response curves for late adverse effects of whole breast and tumour bed boost dose radiotherapy were compared in patients entered into the START pilot fractionation trial (N=1410). In this study, patients were randomised after breast conservation surgery to 13 fractions of 3.0 Gy or 3.3 Gy over 5 weeks to the whole breast. These schedules correspond to dose intensities of 45 Gy and 54 Gy, respectively, in 2.0 Gy equivalents assuming an alb value of 3.0 Gy for late adverse effects. A subset of patients (N=723) was randomised to a tumour bed boost dose of 15.5 Gy in 7 daily fractions using electrons or to no boost. The gradient, expressed at the 50% level of effect as a g50 value, is the absolute % increase in the effect rate per 1% increase in total dose delivered in 2.0 Gy equivalents. Results: The two whole breast test dose levels were associated with a 15.40/0 difference in the risk of change in breast appearance and a 19.6% difference in the risk of moderate or marked breast hardness at 5 years, generating g50 values of 1.0 for change in photographic breast appearance and of 1.3 for moderate/marked induration. Within the randomised subset the boost dose was associated with a 6.2% higher risk of change in breast appearance and to a 13.2% higher risk of moderate or marked breast hardness at 5 years, corresponding to g50 values of 0.2 and 0.4, respectively. Conclusions: The slopes of the dose response curves for late adverse effects after tumour bed boost radiotherapy appear to be shallower than after whole breast radiotherapy, suggesting a significant volume effect that has implications for patients prescribed partial breast and dose escalated whole breast radiotherapy. 9 speaker "ISOTOXIC" INDIVIDUALIZED RADICAL THORACIC RADIOTHERAPY BASED ON NORMAL TISSUE COMPLICATIONS PROBABILITY: FROM DOSE CONSTRAINTS TO MULTIFACTORIAL PREDICTORS P. t.arnbln", C. Oberije ", S. Petit 1 , G. Janssens", W. van Elmpt 1 , D. De Ruysscher ' 1 MAASTRO CLINIC, Radiation Oncology, Maastricht, Netherlands 2 UCL CUNIQUES UNIV. ST.Luc, Communications and Remote Sensing Laboratory (TELE), Brussels, Belgium

It is clear that the risk of Radiation induced lung toxicity (RILT) increases with higher radiation doses on large lung volumes. A rapid increase of the risk seems to occur around a mean lung dose (MLD) of 20 Gy, or a V20 of 35%. The so-called "isotoxic" approaches fixed constraints (e.g. max; MLD = 20 Gy) and esclatae the tumours as much as possible. This approach seems to give excellent results (van Baardwijck et al. JCO 2010). However, the accuracy of both MLD and V20 for the prediction of RILT is very limited with a misclassification of about 35 % of the patients. The present constraints are therefore too strict for some and too loose for others. How to improve the prediction of RILT to better individualized the dose? One approach consists of building a multifactorial predictor including non dosimetric parameters. Within the range of radiation doses used in our clinic, dosimetric parameters play a less important role than patient characteristics (WHO-performance status, smoking status, forced expiratory volume, age) for the prediction of lung toxicity (Dehing et al. R&O, 2009). Another approach takes into account the changes in respiratory status. For example we should not concentrate on dyspnea after therapy but to the delta dyspnea (before and after therapy). To illustrate this point a study (De Ruysscher et al. R&O, 2009) demonstrated that the proportion developing less, the same or more dyspnea 6-9 months post-treatment according to their baseline dyspnea scores was: Grade 0: none, 83%, 17%; Grade 1: 21%, 52%, 27%; Grade 2: 27%,~55°/~ 18%, respectively. Clearly the conclusion of this study is that patients with dyspnea before therapy also have a realistic chance (20-30%) to improve after highdose radiotherapy. Reporting dyspnea at only one time-point post-RT is insufficient to determine radiation-induced dyspnea. Genetic profiles can also be added (e.g. TGFb polymorphism or mitochondrial DNA). The third approach takes into account that the lung is a heterogeneous organ, that is composed of different subunits, whose functional importance varies. Therefore it is likely that the effect of dose to different subvolumes of the lung also varies. Indeed, it has been shown that especially the lower parts of the lung are sensitive to radiation damage. Also the amount of FDG uptake assessed before radiotherapy treatment and the dose to lung regions with baseline increased FDG