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M. Kwint



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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)

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

      • 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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    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: 2
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      MO23.07 - Impact of a gradient-based FDG-PET auto-contouring method on non-small cell lung cancer delineation (ID 1993)

      11:10 - 11:15  |  Author(s): M. Kwint

      • Abstract
      • Presentation
      • Slides

      Background
      Manual target volume delineation using CT/FDG-PET is the standard method used for radiotherapy treatment planning of non-small cell lung cancer (NSCLC) patients. Since manual delineation is prone to inter-observer variability and is time consuming, many FDG-PET auto-contouring methods were proposed in literature. The purpose of this study was to investigate to what extent a gradient-based FDG-PET auto-contouring method reduces observer variation, reduces delineation time and influences delineation behavior in radiotherapy treatment planning for NSCLC patients.

      Methods
      Seven radiation oncologists (observers) dedicated to lung cancer treatment delineated the primary tumor (PT) and involved lymph nodes (LN) for 10 patients with stage IIA-IIIB NSCLC on a co-registered CT/FDG-PET scan. The study was separated in two phases. In the first phase, the observers manually delineated the PT and LN for all patients. For the second phase (four months later), auto-contours were generated for both the PT and LN using a gradient-based FDG-PET segmentation method. Bone and air tissue were removed from these auto-contours using CT thresholding. These auto-contours were provided as initial delineation and were adapted by the observers. Delineation times, delineated contours and agreement with the auto-contour were analyzed. Delineated contours were analyzed based on volume, the ratio between the common volume and the encompassing volume (C/E), Dice Index (DI), local standard deviation (SD) and the local distance between median surface and delineated surface. Regions were identified where the observers did or did not change the provided auto-contours.

      Results
      The observers agreed with the provided auto-contour for 37.3% of the PT and for 42.6% of the LN. Notable regions of agreement were the tumor/bone and tumor/air interfaces. The mean delineation time was reduced by 23.9% from 25.5 minutes in phase 1 to 19.4 minutes for phase 2 (p=0.000). The mean delineated volume was smaller in phase 2 compared to phase 1: 8.9% for the PT (155.8 to 142.0 cm[3], p=0.000) and by 9.1% for the LN (13.2 to 12.0 cm[3], p=0.001), respectively. The C/E ratio and DI both did not change significantly and were 0.79 and 0.88 for the PT and 0.54 and 0.67 for the LN in both phases. The mean local SD for the PT was 1.7 mm and 1.5 mm and for the LN was 1.5 mm and 1.4 mm and both did not change significantly, for both phases respectively. The mean distance between the median surface and PT delineations was slightly reduced from 2.1 to 1.8 mm for phase 2, and was 2.0 mm for the LN in both phases.

      Conclusion
      The gradient-based FDG-PET auto-contouring method reduced delineation time by 24%, but was sufficient in only 37.3% of the primary tumors and 42.6% of the involved lymph nodes; most notably at the tumor/bone and tumor/air interfaces segmented using the CT scan. The results suggest the FDG-PET auto-contour is currently primarily used for localization, and not so much for delineation. Multi-modal auto-contouring has the potential to reduce inter-observer variation when further developed in close collaboration with radiation oncologists.

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      MO23.09 - Intra Thoracic Anatomical Changes (ITAC) in lung cancer patients during the course of radiotherapy (ID 2699)

      11:20 - 11:25  |  Author(s): M. Kwint

      • Abstract
      • Presentation
      • Slides

      Background
      Cone beam-CT (CBCT) guidance is routinely used for setup verification of lung cancer patients treated with radiotherapy. CBCT’s frequently show intra-thoracic anatomical changes (ITAC) during treatment. We developed a protocol as a decision support system to guide the radiation technologist in prioritizing these changes. The purpose of this study was to quantify these ITAC during the radiotherapy course and evaluate the current decision protocol.

      Methods
      The CBCT-scans (made the first 3 fractions and weekly thereafter) of all lung cancer patients treated in 2010 in our institute with radical radiotherapy were evaluated. Each CBCT-scan was visually compared with the planning-CT and all visible ITAC were scored. Additionally, our decision protocol called “traffic-light protocol” was retrospectively applied to all CBCT-scans. The traffic-light protocol has three urgency levels: 1) red: ITAC that likely have a considerable impact on the delivered dose to the primary tumor and/or involved lymph-nodes such as tumor shifts outside the high dose region, large in- or decrease of atelectasis; 2) orange: ITAC with likely moderate impact on the dose distribution such as tumor progression, minor in- or decrease of atelectasis, pleural effusion and post obstructive pneumonia; 3) green: ITAC with likely negligible impact on the dose distribution such as tumor regression without considerable centre of mass displacement or other anatomical changes. For level red changes, the radiation oncologist needs to be consulted immediately before the treatment fraction is delivered. For level orange, the radiation oncologist will be informed by email and a response is required before the next fraction. For level green, the radiation oncologist is informed but no response is required.

      Results
      In total 1500 CBCT-scans of 177 patients were evaluated. All patients received radical radiotherapy (≥50 Gy); 97 patients with concurrent chemoradiation, 23 with sequential chemoradiation and 57 with radiotherapy only. In 128 patients (72%) ITAC were observed with maximum level red, orange and green in 12%, 36% and 24% respectively. Fourteen patients (10%) required a new CT and treatment plan to account for the changed anatomy. Most ITAC occurred in the first week (55%). Of all patients with ITAC during treatment, 45%, 36% and 17% had 1, 2, and ≥3 ITAC respectively. Types of observed ITAC were evident regression (36%), considerable tumor baseline shift (28%), changes in atelectasis (15%), tumor progression (11%), pleural effusion (7%) and pneumonia (3%). Progression seen on the CBCT had a significant correlation with changes in week 1 (p<1e3), and level red changes (p=0.01).

      Conclusion
      ITAC have been observed in 72% of all lung cancer patients during radical radiotherapy. In 12% of the patients the radiation oncologist needed to respond immediately and in 10% of the patients a new planning-CT was made to mitigate the risk of tumor under dosing. Volumetric image guided radiotherapy in combination with a decision protocol is recommended for lung cancer patients treated with radical radiotherapy. In our institute we implemented daily CBCT guidance for accurate patient alignment and simultaneously capture ITAC as soon as possible.

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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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      P2.12-005 - Results of radical treatment of non-small cell lung cancer patients with a single synchronous metastasis (ID 1103)

      09:30 - 09:30  |  Author(s): M. Kwint

      • Abstract

      Background
      Stage IV non-small cell lung cancer (NSCLC) patients are considered incurable and mainly treated for palliation. The purpose of this study is to investigate the overall survival (OS) and disease free survival (DFS) of NSCLC patients, diagnosed with synchronous oligometastatic disease treated with curative intent of the intrathoracic disease as well as the metastasis.

      Methods
      Patients treated between 2008 and 2013 were included in this retrospective analysis. Main inclusion criteria were: synchronous presentation of NSCLC and oligometastatic disease at diagnosis with only 1 extra-thoracic metastasis, and multidisciplinary consent on a radical treatment of both the intrathoracic disease and the solitary metastasis. Treatment of the intrathoracic disease consisted of radical radiotherapy (> 55 Gy biological effective dose) or surgical resection. Treatment of the metastasis consisted of radical/stereotactic radiotherapy or surgical resection or radiofrequency ablation (RFA).

      Results
      Twenty-two patients, 13 men and 9 women, were included. The mean age was 61 years (range 41-79) and all were in good condition (WHO 0-1). The sites of the solitary metastases were brain (13), bone (6), liver (1), soft tissue (1) and adrenal gland (1). The intrathoracic tumor stage (ignoring M-status) was IA in 2 patients, IB in 1 patient, IIA in 4 patients, IIB in 1 patient, IIIA in 8 patients and IIIB in 6 patients. Nineteen patients were treated with radiotherapy and 3 patients had a surgical intervention for the primary tumor. Eighteen patients (82%) received chemotherapy, 3 concurrently and 15 sequentially. The metastases were treated with ablative/stereotactic radiotherapy (19), surgical intervention (2) and RFA (1). The median follow-up was 47 months (95% CI 24-69). Seventeen patients developed recurrent disease of whom 12 died. Only 2 recurrence occurred within the irradiated area. Both infield recurrences were brain metastasis after a stereotactic irradiation of 15 Gy and 18 Gy. The other recurrences where mostly pulmonary (7) and brain metastases (6). The median DFS was 14 months (range 1-47, 95% CI 9 – 19) and the median OS was 32 months (95% CI 12– 52). The 1- and 2-year OS was 78.7% (95% CI 52.7-91.5) and 59.5% (95% CI 32.8-78.5), respectively. The 1- and 2-year DFS was 54.5% (95% CI 30.5-73.2) and 24.9% (95% CI 8.1-46.3), respectively.

      Conclusion
      Radical treatment of a highly selected group of NSCLC patients in good condition presenting with a single synchronous extra-thoracic metastasis resulted not only in adequate local control, but also in favorable long-term DFS and OS.