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Dirk K De Ruysscher



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    GR 02 - Management of Immunotherapy-Related Adverse Events (ID 521)

    • Event: WCLC 2017
    • Type: Grand Rounds
    • Track: Immunology and Immunotherapy
    • Presentations: 1
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      GR 02.07 - Toxicity of Induction Immunotherapy Followed by Radiotherapy: How to Minimize It? (ID 7635)

      11:00 - 12:30  |  Presenting Author(s): Dirk K De Ruysscher

      • Abstract
      • Presentation
      • Slides

      Abstract:
      Checkpoint inhibitors have changed the outcome of patients with metastatic non-small cell lung cancer (NSCLC). Radiotherapy has consistently been shown to activate key elements of the immune system that are responsible for resistance for immune therapy. Radiation upregulates MHC-class I molecules that many cancer cells lack or only poorly express, tumor-associated antigens, provokes immunogenic cell death, activates dendritic cells, decreases regulatory T-cells (Tregs) in the tumor, broadens the T-cell repertoire and increases T-cell trafficking, amongst many other effects. Radiation may convert a completely or partly poorly or non-immunogenic tumor immunogenic. Radiotherapy in combination with different forms of immune therapy such as anti-PD-(L)1, anti-CTLA4,immunocytokines, dendritic cell vaccination and Toll-like receptor agonists improved consistently local tumor control and very interestingly, lead to better systemic tumor control (the “abscopal” effect) and the induction of specific anti-cancer immunity with a memory effect. At the time of writing, the most compelling data in human studies come from Shaverdian et al. (Lancet Oncol 2017). In 97 patients with advanced NSCLC treated on the phase 1 KEYNOTE-001 trial it was shown that patients having received prior radiotherapy, the six-month PFS rate was 54.3% vs. 21.4% among never irradiated patients. The median OS was 11.6 months and the six-month OS estimate was 75.3% among patients who previously received extra-cranial radiation therapy vs. a median OS of 5.3 months and a six-month OS estimate of 45.3% among patients who did not receive extra-cranial radiation therapy. Patients with prior thoracic radiotherapy had more overall pulmonary toxicity compared to never irradiated patients: 12.5% vs. 1.4%. Unfortunately, no dose-volume parameters such as the mean lung dose are available of these patients. The biggest concern of combining radiotherapy and immune treatment is indeed a higher incidence of pneumonitis. Many studies are investigating the combination of radiotherapy, chemotherapy and immune therapy in lung cancer, including the PACIFIC, the STIMULI and the NICOLAS studies. The results of these studies have not been reported at the time of writing, but none of the trials have been closed prematurely. Moreover, as radiotherapy is used to stimulate the immune system, classical concept in dose and volume will have to be investigated again. Less dose in a few fractions may suffice, and margins may be reduced, which in turn will lead to less side effects. When studied meticulously, radiotherapy and immune therapy may well turn out to be efficacious and with few side effects and additional costs.

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    MA 17 - Locally Advanced NSCLC (ID 671)

    • Event: WCLC 2017
    • Type: Mini Oral
    • Track: Locally Advanced NSCLC
    • Presentations: 1
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      MA 17.10 - Toxicity Results from the Randomized Phase III NVALT-11 Study of Prophylactic Cranial Irradiation vs. Observation in Stage III NSCLC (ID 9262)

      15:45 - 17:30  |  Presenting Author(s): Dirk K De Ruysscher

      • Abstract
      • Presentation
      • Slides

      Background:
      NVALT-11 randomized trial showed that PCI reduced the proportion of stage III NSCLC patients with symptomatic BM from 28 % to 5 % (Groen ASCO 2017). Here, we report on the toxicity.

      Method:
      We randomized between PCI or observation in radically treated stage III NSCLC. Primary endpoint: incidence of symptomatic brain metastases; secondary endpoints: OS, toxicity and quality of life.

      Result:
      Between 2009 and 2015 a total of 195 pts were registered, 175 were randomized, 87 received PCI and 88 pts were in the observation arm. Median follow up: 48.5 months (95% CI, 39-54). Neurological adverse events (AE) of all grades that occurred more frequently in the PCI vs. the observation arm: cognitive disturbance (18 vs. 2 pt; p< 10[-4]) and memory impairment (25 vs. 7 pt; p<10[-3]). No significant difference in G3-4 cognitive disturbance and memory impairment. Non-neurological AE of all grades that were more frequent in the PCI arm: alopecia (36 vs. 5 pt; p<10[-6]), fatigue (55 vs. 29 patients; p<10[-4]), nausea (30 vs. 15 patients; p=0.01), anorexia (6 vs. 0 patients; p=0.01) and dysphagia (11 vs. 2 pt; p=0.01). Of the G3-4 AE, only fatigue was significantly more present in the PCI arm (13 vs. 2 pt, p < 0.01). Scored as treatment-related, neurological toxicities of all grades that occurred more frequently in the PCI vs. the observation arm: cognitive disturbance (7 vs. 0 pt; p=0.01), dizziness (7 vs. 0 pt; p=0.01) and memory impairment (14 vs. 0 pt; p<10[-4]). No significant differences in G3-4 toxicities, with only one patient reporting severe cognitive disturbance in the PCI group. Scored as treatment-related, non-neurological toxicities of all grades that were more frequent in the PCI arm: alopecia (26 vs. 1 pt; p<10[-6]), fatigue (19 vs. 2 patients; p<10[-4]), nausea (16 vs. 0 patients; p<10[-5]), headache (19 vs. 1 pt; p<10[-5]), rash (8 vs. 0 pt; p<0.01) and vomiting (9 vs. 0 pt; p<0.01). No significant differences in G3-4 toxicities, with 3 patients reporting severe fatigue, 2 nausea and 1 vomiting, all in the PCI group. Overall Qol was worse in the PCI arm 3 months post-treatment, but was similar to observation thereafter.

      Conclusion:
      PCI related symptoms were mainly grade 1-2 memory and cognitive disturbances and fatigue. G3-4 toxicities were very rare. QoL was only temporarily affected by PCI. The side effects of PCI should be balanced against deteriorating BM symptoms and the lack of OS benefit (Groen ASCO 2017).

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    P1.13 - Radiology/Staging/Screening (ID 699)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Radiology/Staging/Screening
    • Presentations: 1
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      P1.13-007 - Is Central Lung Tumor Location Really Predictive for Occult Mediastinal Nodal Disease in (Suspected) NSCLC Staged cN0 on PET-CT?  (ID 8779)

      09:30 - 16:00  |  Author(s): Dirk K De Ruysscher

      • Abstract

      Background:
      Based on a 20-30% prevalence of occult mediastinal disease, current guidelines recommend preoperative invasive mediastinal staging in patients with central tumour location and negative mediastinum on PET-CT. A uniform definition of central tumour location is lacking. Our objective was to determine the best definition in predicting occult mediastinal disease.

      Method:
      A single institution prospective database was queried for patients with (suspected) NSCLC staged cN0 after PET-CT and referred to invasive staging and/or primary surgery. We evaluated 5 definitions of central tumour location (table 1).

      Result:
      Between 2005 and 2015, 822 patients were eligible. Radio-occult lesions were excluded from analysis (n=9). Preoperative histology was NSCLC in 49% and unknown in 51%. The lesion was subsolid in 7%. Tumour stage was cT1, cT2, cT3 and cT4 in 43%, 28% 17% and 11%, respectively. Invasive mediastinal staging (EBUS and/or mediastinoscopy) was performed in 31%. Surgical resection was performed in 97%, a median of 5 (IQR 3-6) nodal stations were examined. The final pathology was squamous NSCLC, non-squamous NSCLC, or other in 38%, 54% and 7%, respectively. Any nodal upstaging was found in 21% (13% pN1 and 8% pN2-3). Central tumour location demonstrated, compared to peripheral location, a 4 times higher risk for any nodal upstaging but not for N2-3 upstaging (table 1).

      Conclusion:
      When modern PET-CT fusion imaging points at clinical N0 NSCLC, the prevalence of occult mediastinal nodal disease was only 8% in our patient cohort. None of the five definitions of centrality we studied was predictive for occult pN2-N3. Overall nodal upstaging was 21%, however, and all definitions of centrality then had discriminatory value. These data question whether the indication of preoperative invasive mediastinal staging should be based on centrality alone. Table 1 Figure 1



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    P2.08 - Locally Advanced Nsclc (ID 709)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Locally Advanced NSCLC
    • Presentations: 2
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      P2.08-001 - Hand Grip Strength Is an Independent Prognostic Factor for Mortality in Patients with NSCLC Undergoing Radiotherapy (ID 9095)

      09:30 - 16:00  |  Presenting Author(s): Dirk K De Ruysscher

      • Abstract

      Background:
      Loss of muscle mass and function is common in patients with non-small cell lung cancer. Handgrip strength is a simple screening measure of general limb muscle function which is clearly associated with mortality in the general population and in some chronic disease populations. It is largely unclear to what extent handgrip strength provides prognostic information in patients with non-small cell lung cancer.

      Method:
      Handgrip strength was bilaterally assessed with a Jamar handheld dynamometer before initiation of radiotherapy. Normative values for handgrip strength have been proposed based on centile scores in over 224,000 healthy adults, adjusted for age, sex, height and measurement side. Patients were defined as weak if handgrip strength at one side (left or right) was below the tenth centile of the general population. Cox proportional hazard models were used to assess the relationship between handgrip weakness and mortality. Follow-up time was calculated from the day of assessment. Results are reported unadjusted and adjusted for disease stage (I to IV), World Health Organization Performance Score (WHO PS), gender and age.

      Result:
      We included 1497 patients for analysis (age 68±10; 63% male; stage I:17%; II:9%; III:60%; IV:14%). During follow-up 1109 patients (74%) deceased (time to death 18 ±17 months); mean follow-up in survivors was 46±25 months. Baseline weakness was present in 29% of patients. Unadjusted analysis shows an association between handgrip weakness and mortality (HR 1.64 (1.45-1.86; p<0.001; see figure 1). After covariate adjustment, handgrip weakness remained significantly related to mortality (HR 1.46 (1.27-1.68; p<0.001). Figure 1. Figure 1



      Conclusion:
      Our findings suggest that handgrip strength provides prognostic information in addition to well-established prognostic markers including disease stage, functional performance score and age in NSCLC patients who undergo radiotherapy. The detection of handgrip weakness is easy and quick and therefore might have a role in routine pre-treatment screening in this patient group.

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      P2.08-007 - Five-Year Results of Concurrent Chemotherapy and Isotoxic Radiotherapy Dose-Escalation with IMRT in Stage III NSCLC (NCT01166204) (ID 9261)

      09:30 - 16:00  |  Presenting Author(s): Dirk K De Ruysscher

      • Abstract
      • Slides

      Background:
      Previous studies by our group showed that that increasing the radiotherapy (RT) dose in an overall treatment time (OTT) of less than 6 weeks on basis of the isotoxic principle is feasible and could potentially increase the overall survival (OS) with non-concurrent chemo-RT without increasing the toxicity. No data were yet available for IMRT treated patients.

      Method:
      From 04-05 2009 until 26-04-2012, 185 patients with stage III NSCLC, treated with concurrent chemo-RT were included in this single center phase II trial. OS update was done on June 7, 2017. The primary endpoint of this study was OS, with in-field nodal failures (INF) and toxicity as secondary endpoints. Patients received 1 cycle of cisplatin-etoposide followed by two cycles of the same chemotherapy with concurrent radiotherapy (IMRT, 45 Gy BID followed by 2 Gy QD to the maximal organ at risk constraint).

      Result:
      Patient characteristics: Gender: Male: 61.1 %, Female: 38.9 %. Age 63.9 ± 8.9 years (44-86). Smoking: Never 2.9 %, current 36.8 %, former 60.3 %. WHO performance status: 0 (36.2 %) 1 (56.8 %), 2 11 (5.9 %), 3: 1 pt , 4:1 pt. Histology: Squamous 55 (29.7 %), Adenocarcinoma 49 (26.9 %), Large cell 26 (14.1 %), NSCLC-NOS 55 (29.7 %). GTV (T+N) 120.4 ± 132 ml (16.8-708.5), Total Tumor Dose 66.0 ± 12.8 Gy (36.0-73.0).Number of fractions: 39.7 ± 3.4 (24-44). OTT 38.2 ± 26.8 days (16-93) MLD 17.3 ± 3.0 Gy (4.9-21,2). Mean Esophageal Dose 29.0 ± 9.3 Gy (6.3-54.1). OS: stage IIIA (n=42), median 16.7 Mo (8.7-24.7), 5-year 16.7 %; stage IIIB (n=143) 20.3 (16.2-24.4), 5-year 27.3 % (P=0.10). INF: 3/185 (1.6 %). Loco-regional failures: 59/185 patients (31.8 %) Toxicity: Dyspnea Grade Baseline Maximal score 0 102 (55.1 %) 71 (38.4 %) 1 68 (36.8 %) 103 (55.7 %) 2 15 (8.1 %) 5 (2.7 %) 3 0 6 (3.2 %) 88% of patients experienced any grade of dysphagia: 22% experienced grade 1 dysphagia, 44% grade 2, while 22% experienced grade 3 dysphagia.

      Conclusion:
      Isotoxic accelerated radiotherapy delivered with IMRT and concurrently with chemotherapy leads to low INF and toxicity is comparable to the best series using standard fractionation schedules. Long term OS remains low and therefore other strategies are needed.

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    P3.09 - Mesothelioma (ID 725)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Mesothelioma
    • Presentations: 1
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      P3.09-003 - Heart Radiation Dose as a Risk Factor for Dyspnea Worsening After Multimodality Treatment for NSCLC and MPM: An Exploratory Analysis (ID 10496)

      09:30 - 16:00  |  Author(s): Dirk K De Ruysscher

      • Abstract

      Background:
      The purpose of our study was to quantify the influence of heart dose on the early and late onset of dyspnea in a cohort of non-small cancer (NSCLC) and malignant pleural mesothelioma (MPM) patients having multimodality treatment including radiotherapy (RT).

      Method:
      In 121 patients with multimodality-treated NSCLC and MPM the maximal dyspnea score (CTCAE 4.0) before RT, at an early (<6 months) and a late (7-12 months) time point were obtained. Included patients needed to be clinically and radiologically progression-free 9 months after the end of RT. The difference (Δ) between the maximal dyspnea at <6 months and at 7-12 months with the pre-RT dyspnea was calculated.

      Result:
      Forty-four percent (50/113) of the patients developed an early worsening of at least 1 point in their dyspnea score (Δdyspnea >1) after the end of RT. Independent predictors of an early worsening were the mean heart dose (MHD) (for Δdyspnea >1: OR=1.03, p=0.04) and the dyspnea score before RT (for Δdyspnea >1: OR=0.40, p=0.0001; for Δdyspnea >2: OR=0.35, p=0.05). At the later time point, only the dyspnea score before RT (OR: 0.40, p=0.001) was identified as predictor of Δdyspnea >1.

      Conclusion:
      Our results, albeit exploratory, suggest that heart dose may play a role in the early worsening of the dyspnea in a heterogeneous cohort of patients having multimodality treatment including RT, whereas baseline dyspnea plays a major role for both early and later worsening.

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    P3.14 - Radiotherapy (ID 730)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Radiotherapy
    • Presentations: 1
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      P3.14-011 - Mean Heart Dose Is an Independent Risk Factor for Early Mortality After Chemoradiotherapy Treatment for Lung Cancer (ID 10342)

      09:30 - 16:00  |  Presenting Author(s): Dirk K De Ruysscher

      • Abstract
      • Slides

      Background:
      Early mortality after (chemo)radiotherapy can be caused by treatment-related toxicities and thus by delivered doses to normal lung and heart tissues. However, prediction models for mortality incorporating dosimetry are lacking. This study explores the prognostic value of common dosimetric features.

      Method:
      Two prospective cohorts containing 218 and 181 curatively treated stage I-III lung cancer patients from 2003-2007 and 2013-2016 periods, respectively, were studied. Prescribed dose was 66Gy/2Gy (concurrent chemotherapy), 66Gy/2.75Gy (sequential or no chemotherapy) or a similar schedule. Clinical (WHO performance status, age, T stage, N stage and primary gross tumor volume (GTV)) and dosimetric (mean lung dose (MLD) and mean heart dose (MHD)) covariates were analysed. Cox regression models of survival and a logistic regression model for the 12 month mortality endpoint were optimized using forward stepwise selection (p<0.05).

      Result:
      Median follow-up time was 80.2 and 20.2 months in dataset 1 and 2, respectively. MHD (HR=1.023, p=0.001) and WHO performance status (HR=1.25, p=0.03) were selected in the Cox model for dataset 1. Tumor volume (HR=1.0015, p=0.001), WHO performance status (HR=1.023, p=0.02) and MHD (HR=1.0030, p=0.03) were selected in dataset 2. Adding time-dependent covariates revealed a decreasing GTV HR over time in dataset 1 (p=0.02), while MHD risk did not significantly change with time. Worse survival observed in a high MHD subgroup indeed only starts after 8 months (Figure 1). 12 month survival modeling included the covariates MHD (optimal cut-off 22Gy) and GTV (AUC=0.71). In dataset 2, these covariates and cut-off resulted in a model with AUC=0.63. Figure 1



      Conclusion:
      Mean heart dose is an independent risk factor for early mortality in two cohorts with different treatment periods and techniques. The best classifier for 12 month mortality risk was obtained with the MHD<22Gy constraint, which could be used in model-based implementation of proton therapy.

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