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D. De Ruysscher



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    Symposium supported by IASLC Radiotherapy Group (ART): What is the Appropriate Patient Population for IGRT? (Simultaneous translation English >< Mandarin provided) (ID 246)

    • Event: WCLC 2013
    • Type: Industry Supported Symposium
    • Track:
    • Presentations: 1
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      How I do it: Dose, volume, motion management. (ID 5673)

      07:00 - 07:20  |  Author(s): D. De Ruysscher

      • Abstract
      • Slides

      Abstract not provided

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

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Radiation Oncology + Radiotherapy
    • Presentations: 1
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      MO23.10 - Addition of EBUS-mapping of the mediastinum to PET/CT based selective nodal irradiation in NSCLC decreases geographical miss and nodal GTV volume (ID 2841)

      11:25 - 11:30  |  Author(s): D. De Ruysscher

      • Abstract
      • Presentation
      • Slides

      Background
      FDG-PET/CT based selective lymph node (LN) irradiation is the standard when using 3D-conformal techniques (3D-CRT) for locally advanced NSCLC. With 3D-CRT, adjacent LN not included in the target volume still receive a substantial radiation dose. With current new techniques (IMRT/VMAT), the radiation dose to non-involved LN decreases, which raises the question whether selective nodal irradiation based on PET/CT is still safe. We therefore evaluated the impact of adding EBUS-TBNA (endobronchial ultrasound guided transbronchial needle aspiration)-mapping of the mediastinal LN to PET/CT in avoiding geographical miss, and on the size of nodal GTV (gross tumor volume).

      Methods
      Consecutive NSCLC-patients referred for radiotherapy (RT) in 2012 who underwent EBUS-TBNA were included. False negative (FN) LN for different constellations of PET, CT and EBUS-TBNA based on literature data were calculated, to evaluate the safety of excluding LNs based on CT, PET and EBUS findings. A practical algorithm when to include LN in the GTV was made, and tested on our patients. Results are expressed as mean +/- SD and range.

      Results
      Twenty-five consecutive patients with a full EBUS-TBNA mapping before RT were included: 11 women, 14 men; 17 adenocarcinoma, 8 squamous cell carcinoma; 14 right-sided and 11 left-sided tumors. Mean age: 62.5 +/- 9.7 years. All patients had stage III-disease based on PET-CT. LN stations 1,2R,2L,3,4R,4L,5,6,7,8,9,10-11L,10-11R were analyzed on CT- and PET-scan (=325 LN). Sixty-seven were enlarged (≥10mm), of which 63 were PET-positive. Twelve normal-sized LNs were PET-positive. Fifty LNs were investigated with EBUS-TBNA (mean: 2/patient +/-0.96;1-5): 28 were malignant, 22 normal. EBUS-TBNA detected 1 cancer-containing normal-sized LN without FDG-uptake, thus 1/25 geographical miss (4%). The cancer prevalence, taking into account the FN rate of EBUS of 20%, was calculated (Fig.1). With addition of EBUS, in PET-negative patients FN decreases with 10% for enlarged LN, and with 5% for normal-sized LN. An algorithm when to include a LN in the GTV is proposed (Fig.1). According to this algorithm, in our population 3/79 (4%) enlarged or PET-positive LN would be excluded from the GTV. At patient level, this was a GTV decrease in 3 (12%) patients.

      Conclusion
      When incidental nodal irradiation is low such as in IMRT or VMAT, EBUS-TBNA should be added to FDG-PET/CT for mediastinal staging. This avoids geographical miss in 4% of patients, and decreases the radiation volume in 12% of patients. A practical algorithm is proposed.

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    MO25 - NSCLC - Combined Modality Therapy II (ID 112)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Mesothelioma
    • Presentations: 1
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      MO25.07 - Early onset body weight loss during concurrent chemo-radiotherapy for non-small cell lung cancer is not due to dysphagia or reduced calorie intake (ID 3409)

      11:10 - 11:15  |  Author(s): D. De Ruysscher

      • Abstract
      • Presentation
      • Slides

      Background
      Increased treatment-associated esophagitis could be responsible for concurrent chemo-radiotherapy (CT-RT)-induced weight loss in patients with non-small cell lung cancer (NSCLC). However, based on clinical observations, we hypothesized that weight loss already starts early after initiation of concurrent CT-RT and might therefore be not solely dependent on decreased intake due to esophagitis symptoms.

      Methods
      In a retrospective cohort, the onset and frequency of weight changes and their association with esophagitis grade ≥2 were assessed in patients with NSCLC treated with concurrent (n=102) or sequential (n=92) CT-RT. The findings in the retrospective cohort were validated in a prospective study in which weight loss and esophagitis grade ≥2 was assessed over a longer time period and additional data on nutritional intake, muscle strength and quality of life was obtained of patients treated with concurrent CT-RT (n=9).

      Results
      In the retrospective cohort, both the number of patients with weight loss and the magnitude of weight loss was significantly higher in concurrent than sequential treated patients in week 2, 3 and 4 of (CT-)RT (p<0.05). Longitudinal data analysis showed no significant associations between weight loss and grade esophagitis ≥2 in patients treated with concurrent CT-RT (p=0.10). In the prospective cohort, a similar pattern of ‘early’ weight loss was observed in the first weeks of concurrent CT-RT (p<0.05). This early weight loss was not accompanied by significant decreases in nutritional intake but muscle strength did already decline in this early stage (p<0.05). In the following weeks of concurrent CT-RT, the weight further decreased and reached its minimum at the end of treatment (p<0.05), while the number of patients with grade esophagitis ≥2 increased during this time period. During the later part of concurrent CT-RT, dietary intake was significantly lower and patients became more reliant on supplemental nutrition (p<0.05). Although the weight increased again in the weeks after concurrent CT-RT, it had still not reached the baseline level after 4 weeks post treatment (p<0.05).

      Conclusion
      Weight loss is a common complication of concurrent CT-RT for locally advanced NSCLC, starts early after initiation of CT-RT and is not dependent of esophagitis. It is presumably caused by active catabolism as this ‘early’ weight loss is accompanied by decreased muscle strength, despite stable dietary intake. In the later weeks of treatment, concurrent CT-RT is characterized by a further decline in body weight, decreased dietary intake and higher reliance on nutritional support. In this phase the occurrence of radiation-induced esophagitis grade ≥2 increases. In the weeks following concurrent CT-RT, partial recovery of body weight takes place but this is still not complete after 4 weeks post CT-RT. The sustained weight loss during and following concurrent CT-RT might have major negative consequences as weight loss in patients with underlying malignant disease might has been associated with higher mortality, lower treatment responses and decreases in quality of life. Though the origin of weight loss during concurrent CT-RT seems to be different in the subsequent phases, more aggressive supportive nutritional support throughout the treatment course seems conceivable to prevent negative energy balances and optimize concurrent CT-RT management.

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    P1.08 - Poster Session 1 - Radiotherapy (ID 195)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Radiation Oncology + Radiotherapy
    • Presentations: 2
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      P1.08-014 - PET-based radiotherapy planning is highly cost-effective compared to CT-based planning: a model-based evaluation. (ID 1608)

      09:30 - 09:30  |  Author(s): D. De Ruysscher

      • Abstract

      Methods
      The cost-effectiveness analysis was performed using a previously developed decision model that simulates the disease progression of individual lung cancer patients until they are deceased or have reached a pre-specified time-horizon of 3 years. Simulated patients move from the start of radiotherapy treatment to the absorbing state of death, potentially visiting the intermediate health states ‘local recurrence’ and ‘metastasis’. Transition rates in the model were estimated by multi-state statistical modelling and include the impact of patient and tumour features on disease progression. Data for model quantification was available for 200 NSCLC patients with inoperable stage I-IIIB, provided by the Maastro Clinic. Resource use estimates, costs and utilities were obtained from the data of the Maastro Clinic, the literature and Dutch guidelines. Primary outcomes were the difference in life years, quality adjusted life years and costs and the incremental cost-effectiveness and cost-utility ratio (ICER and ICUR) of PET-CT versus CT based radiotherapy planning. Model outcomes were obtained from averaging the outcome for 50 000 simulated patients. A probabilistic sensitivity analysis was done as well as a number of scenario analyses.

      Results
      The incremental costs of PET-CT based planning were €581 (95% CI: €-4474 – €6064) for 0,42 incremental life years (95% CI: 0,20 – 0,62) and 0,33 quality adjusted life years gained (95% CI: 0,16 – 0,54) (figure 1). The base-case scenario resulted in an ICER of €1370 per life year gained and an ICUR of €1761 per quality adjusted life year gained. The probabilistic analysis gave a 35% probability that PET-CT based planning improves health outcomes at reduced costs and a 65% probability that PET-CT based planning is more effective at slightly higher costs.Figure 1 Figure 1. Results of probabilistic sensitivity analyses showing incremental costs and incremental life years for PET-CT-based radiotherapy treatment planning compared to CT-based radiotherapy treatment planning.

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      P1.08-022 - Number of pathologic nodes in regions closest to the oesophagus is the strongest predictor for esophagitis in small cell lung cancer patients treated with concurrent chemo-radiation: an analysis of 170 patients. (ID 2711)

      09:30 - 09:30  |  Author(s): D. De Ruysscher

      • Abstract

      Background
      Radiation esophagitis grade III caused by chemo-radiation for small-cell lung cancer is a burden for patients and thus of concern to radiation oncologists. Neutropenia and radiation dose to the esophagus are known treatment factors influencing the rate of esophagitis during treatment, but currently the only factors that can be discussed with the patient at diagnosis are the choice of concurrent versus sequential chemo-radiation and the radiation dose fractionation schedule. In order to build predictive models to more accurately tailor treatment and advise patients on treatment options, more prognostic factors known at the moment of diagnosis are needed.

      Methods
      Analysis of all patients in our prospective database with stage I-III SCLC referred for concurrent chemo-radiotherapy between 5-2004 and 1-2012. All patients were PET-staged and received 45 Gy in 1.5 Gy fractions twice daily to the tumour and PET-or pathologically proven positive lymph nodes. Chemotherapy consisted of carboplatin-etoposide given concurrently with radiotherapy. All pathological lymph node regions were noted for each patient. Based on the Mountain Dressler atlas, the lymph node regions closest to the oesophagus were designated ``high risk`` regions for esophagitis, namely: 1R, 1L, 3P, 4L, 7, 8 and 9. Toxicity was scored according to CTC AE 3.0. Univariate analysis was done using the Chi-square test, reporting for p-value the Fischer exact Test for small numbers of events. Multivariate analysis was done using logistic regression. .

      Results
      170 patients were included in the present analysis. Thirty-seven (20%) patients developed grade III esophagitis. In univariate analysis the number of nodal regions (0, 1-4, ≥5) (p=0.02) and the number of high risk nodal regions (0, 1-2, ≥3) (p=0.001) had a significant effect on the risk of grade III esophagitis whereas the location of the primary tumour or having a T4 tumour did not. In multivariate analysis including age, gender and T4 tumour, the number of pathological nodal stations lost significance. In the multivariate analysis using age, gender, T4 tumour and the ``high risk`` count (0, 1-2, ≥3 areas) having nodes in ≥3 high risk areas was the only significant factor (p=0.002), with a hazard ratio (HR) of 7.4 for developing oesophagitis grade III (95% CI for HR: 2.2-25.2). The absolute rates of esophagitis grade III were: 5/51 (10%), 19/91 (21%), 12/28 (43%) for patients with respectively 0, 1-2 and ≥3 pathological high risk nodal areas.

      Conclusion
      In this series of stage I-III small cell lung cancer treated with radical chemo-radiation, the strongest predictor for esophagitis grade III known at diagnosis is the presence of nodal disease in ``high-risk regions`` 1R, 1L, 3P, 4L, 7, 8 and 9. Analysis of the correlation of this finding with the dose to the esophagus (Dmax/ Dmean) is ongoing and will also be presented at the conference.

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    P2.08 - Poster Session 2 - Radiotherapy (ID 198)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Radiation Oncology + Radiotherapy
    • Presentations: 1
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      P2.08-002 - Modern post-operative radiotherapy for stage III non-small cell lung cancer may improve local control and survival: A publication-based meta-analysis (ID 89)

      09:30 - 09:30  |  Author(s): D. De Ruysscher

      • Abstract

      Background
      We hypothesized that modern postoperative radiotherapy (PORT) could decrease local recurrence (LR) and improve overall survival (OS) in patients with stage IIIA-N2 non-small-cell lung cancer (NSCLC).

      Methods
      To investigate the effect of modern PORT on LR and OS, we identified published phase III trials for PORT and stratified them according to use or non-use of linear accelerators. We modelled the potential benefit of modern PORT in stage IIIA-N2 NSCLC treated with induction chemotherapy and resection.

      Results
      Of the PORT phase III studies, eleven trials (2387 patients) were included for OS analysis and eight (1677 patients) for LR. PORT decreased LR, whether given with cobalt, cobalt and linear accelerators, or with linear accelerators only. An increase in OS was only seen when PORT was given with linear accelerators, along with the most significant effect on LR (relative risk for LR and OS 0.31 (p=0.01) and 0.76 (p=0.02) for PORT vs. controls, respectively). Four trials (357 patients) were suitable to assess LR rates after surgery and/or induction chemotherapy in stage III NSCLC. LR as first relapse was 30 % (105/357) after 5 years. In the modelling part, PORT with linear accelerators was estimated to reduce LR rates to 10 % as first relapse and to increase the absolute 5-year OS by 13 %.

      Conclusion
      This modelling study generates the hypothesis that modern PORT may increase both LR and OS in stage IIIA-N2 NSCLC even in patients being treated with induction chemotherapy and surgery.

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    P3.08 - Poster Session 3 - Radiotherapy (ID 199)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Radiation Oncology + Radiotherapy
    • Presentations: 1
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      P3.08-014 - Very high radiation dose escalation in NSCLC does not lead to unexpected toxicity: A planned toxicity analysis of the PET-boost study (NCT01024829) (ID 1925)

      09:30 - 09:30  |  Author(s): D. De Ruysscher

      • Abstract

      Background
      Locoregional failure rates are high in patients with locally advanced non-small cell lung cancer (NSCLC), even when using concurrent chemoradiation. Recurrences have been shown to be predominantly located in the primary tumor, more specifically in areas with a high FDG-uptake that can be identified on a pre-treatment FDG PET-CT scan. Improved tumor control could be accomplished by dose escalation. The PET-boost trial is an ongoing randomized phase II trial investigating radiation dose-escalation using an individualized, accelerated schedule either to the entire primary tumor or to the regions of high FGD-uptake (>50% SUVmax) within the primary tumor. We present a preliminary analysis of the acute toxicity of the first 45 patients.

      Methods
      Patients with NSCLC stage IB-III with a primary tumor diameter ≥4 cm are eligible. Patients are treated with concurrent or sequential chemoradiation or radiotherapy only. Permitted regimens are: daily dose cisplatin (only in concurrent chemoradiation) or cisplatin-etoposide in concurrent and sequential chemoradiation. Eligible patients receive a planning PET-CT scan on which an IMRT plan is constructed up to a dose of 66 Gy in 24 fractions of 2.75 Gy to the involved lymph nodes and the primary tumor. In patients where normal tissue constraints allow further dose escalation to the primary tumor up to a minimal dose of 72 Gy of ≥ 3 Gy-fractions, 2 plans (with equal mean lung dose) are constructed: either giving the integrated boost to the entire primary tumor (Arm A) or redistributing the boost to areas of high FGD-uptake (>50% SUVmax) in the tumor (Arm B), up to a maximal prescribed dose of 129.6 Gy in 24 fractions of 5.4 Gy. All pts are followed according to study protocol. Toxicity is scored according to the CTCv3.0 criteria. Primary endpoint of this study is local progression-free survival at 1 year. Secondary endpoints are acute and late toxicity, overall survival and quality of life.

      Results
      Between 2010 and 2013 71 patients were registered of which 45 were randomized: 22 pts to arm A and 23 to arm B. In both arms, median follow up was 13.3 months. Patient and tumor characteristics were equally distributed in both arms. Thirty-seven patients (82.2%) had stage III lung cancer. Concurrent chemoradiotherapy was given in 25 patients (55.6%). Mean GTV was 154.2 cm ³ (range 26-416 cm³). Mean fraction size in both arms was 3.46 Gy (range 3.0-5.4 Gy). Baseline toxicity grade 3 occurred in 4 patients (8.8%) consisting of dyspnea in 1 patient, cough in 2 patients and renal dysfunction in 1 patient. During treatment grade ≥3 hematologic toxicity was seen in 6 patients (13.3%), whereas 2 patients (4.4%) suffered from cardiac toxicity grade 4 (ischemia/infarction). Seven patients (15.6%) had grade ≥3 dysphagia. 82.2% of the patients finished treatment according to study protocol. Radiation treatment was completed in all patients. Seven patients have died of which 3 (6.6%) due to pulmonary hemorrhage.

      Conclusion
      This first toxicity analysis of the multicenter phase II randomized PET-boost trial at a median follow up of 13.3 months did not reveal any unexpected acute or late toxicity.

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    P3.09 - Poster Session 3 - Combined Modality (ID 214)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Combined Modality
    • Presentations: 1
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      P3.09-004 - Oligometastatic non-small cell lung cancer: a simulation expert multidisciplinary tumor board. (ID 1122)

      09:30 - 09:30  |  Author(s): D. De Ruysscher

      • Abstract

      Background
      Series on aggressive local treatment in selected patients with oligometastatic non-small cell lung cancer (NSCLC) are mostly retrospective, and prospective data are scarce (De Ruysscher et al, JTO 7:1547-1555, 2012). Although a precise definition is lacking, ‘oligometastatic NSCLC’ is considered an intermediate biologic state of restricted metastatic capacity with a limited number of metastases. The turning point between oligometastatic and polymetastatic is merely based on personal opinion and situated somewhere between 1 and 5 distant metastases. In the absence of clear definitions or clinical practice recommendations, a treatment decision is mainly driven by the opinion of each local multidisciplinary tumor board (MDTB).

      Methods
      As the consideration of and the treatment modality for oligometastatic NSCLC is a controversial area in respiratory oncology, in preparation of a recent dedicated workshop, we simulated a MDTB with international experts in the field. Multiple disciplines from 7 different centers participated in the MDTB, including pathology (1), nuclear medicine physician (1), thoracic surgery (3), radiation oncology (3), and respiratory oncology (3). Participants were asked to assess an electronic file describing 10 clinical ‘oligometastatic NSCLC’ cases, with 2 simple questions per case: 1. Do you consider this case ‘oligometastatic’ (Yes/No) and 2. What is your preferred treatment proposal.

      Results
      A full response was returned by all 11 specialists taking part in the simulated MDTB. Only 1 case was considered ‘oligometastatic NSCLC’ by all MDTB members. The presented cases were considered by a median of 78% (range 36-100%) of responders as true oligometastatic disease. Despite the fact that each responder gave only one treatment proposal, a median of 4 different treatment proposals (range 2-6) was made per case. Except for brain metastases, most team members would treat the locoregional thoracic disease before the distant metastases. No preference towards neo-adjuvant or adjuvant chemotherapy could be found. The option for surgery or radiation therapy as part of a combined modality treatment was mainly driven by the physicians’ preference.

      Conclusion
      Our simulated MDTB shows that oligometastatic NSCLC is an entity with many unanswered questions, and thus a major challenge for clinicians. Patients with oligometastatic NSCLC are in the need of 1. discussion at an experienced multidisciplinary tumor board to select patients for a radical combined modality approach; 2. multidisciplinary prospective research protocols to set better definitions of oligometastic NSCLC, evaluate the validity of a radical approach, and to optimize therapeutic modalities.