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J. Nijkamp



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    E02 - Radiation Toxicity (ID 2)

    • Event: WCLC 2013
    • Type: Educational Session
    • Track: Radiation Oncology + Radiotherapy
    • Presentations: 1
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      E02.2 - Radiation Esophagitis (ID 378)

      14:00 - 15:30  |  Author(s): J. Nijkamp

      • 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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    O10 - Stereotactic Ablative Body Radiotherapy (ID 104)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Radiation Oncology + Radiotherapy
    • Presentations: 1
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      O10.07 - Dose-response analysis of radiation induced rib fractures after SBRT for NSCLC (ID 2690)

      16:15 - 17:45  |  Author(s): J. Nijkamp

      • Abstract
      • Presentation
      • Slides

      Background
      Symptomatic rib fractures occur in approximately 5% of patients treated with SBRT for early stage NSCLC. Only in small patient cohorts has the dose-effect relation of radiation induced rib fractures been determined. Recent developments in automatic rib segmentation allow determining the dose-effect relation in a large patient cohort, which is the aim of this study.

      Methods
      From 2006-2012 453 patients with early stage NSCLC were treated with SBRT (3x18 Gy). Follow-up (FU) consisted of a physical examination and a CT scan 4 months after treatment and every 6 months up to two years and yearly thereafter. For the first 101 patients with FU>6 months, all ribs were automatically segmented using 15 atlases of manually delineated ribcages. A non-rigid registration followed by a multi-level label fusion produced for each patient a set of ribs. The physical dose distributions were NTD (Normalized Total Dose) corrected with α/β=3 Gy. Cox proportional hazard regression analysis, which takes into account the time to event with patient as random intercept, was used to find the optimal dose parameter. Evaluated were the dose received by x% of the rib D~x~ (x ranged 1-30%) and equivalent uniform dose (EUD) (volume effect 1/n ranged 0.1-60). The Lyman-Kutcher-Burman (LKB) model based on this optimal dose parameter was used to model the dose-effect relationship. Using maximum-likelihood estimation, parameters were median toxic dose (TD~50~), steepness parameter m and 1/n were optimized.

      Results
      In 354 patients with FU>6 months (median 22 months), 38 patients(11%) were diagnosed with a total of 49 rib fractures, symptomatic (grade 2) for 9 patients(2.5%). Included in the dosimetric analysis were 2410 ribs (14 ribs outside field-of-view). 26 ribs in 15 patients(15%) were fractured, symptomatic for 4 patients(4%). In the univariate analysis, all dose parameters significantly correlate with rib fracture (p-values<0.001). Hazard ratios (95%CI) for the parameters with highest log likelihood: D~1~=1.022 (1.017-1.027) and EUD~0.033~=1.021 (1.016-1.026). Multivariate analysis identified EUD as the predictor with the highest log-likelihood and was used in the LKB model. The optimal LKB parameters to predict rib fracture in this dataset were (95% CI): TD~50~=395.5 Gy (244.3-555.1), m=0.348 (0.311-0.384) and 1/n=32.3 (4.82-inf). The risk of rib fracture was <5% in case the NTD-corrected EUD<170 Gy.Figure 1

      Conclusion
      In this subgroup of NSCLC patients treated with 3x18Gy, the risk of rib fracture was significantly correlated to the dose, and was <5% in case the biological dose is kept under 170 Gy.

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