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D. De Ruysscher
Moderator of
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ORAL 19 - Radiation for Localized Lung Cancer (ID 126)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Localized Disease - NSCLC
- Presentations: 8
- Moderators:D. De Ruysscher, M. Hiraoka
- Coordinates: 9/08/2015, 10:45 - 12:15, 102+104+106
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ORAL19.01 - The SPACE Study: A Randomized Phase II Trial Comparing SBRT and 3DCRT in Stage I NSCLC Patients; Final Analysis including HRQL (ID 923)
10:45 - 10:56 | Author(s): A. Hallqvist, J.A. Lund, O.T. Brustugun, B. Bergman, P. Bergström, S. Friesland, R. Lewnsohn, N. Drugge, H. Rylander, I. Lax, E. Holmberg, J. Nyman
- Abstract
- Presentation
Background:
Stereotactic body radiotherapy (SBRT) for NSCLC patients with T1-T2 tumors has been intensively studied the last decades and is widely used due to excellent results in terms of local control and survival in combination with the convenient and fast treatment procedure. This radiation technique has however never been compared to standard radiotherapy in a randomized manner, and consequently the Swedish lung cancer study group launched the SPACE study in 2007 (Stereotactic Precision And Conventional radiotherapy Evaluation).
Methods:
Patients with stage I medically inoperable histologically confirmed NSCLC or PET-positive tumors with progression (non-centrally located with a maximum size < 5 cm) were randomized in 9 Scandinavian centers to receive SBRT to 66 Gy in 3 fractions in one week or conventionally fractionated 3DCRT to 70 Gy in 7 weeks. Patients were followed with regard to treatment efficacy, toxicity and HRQL.
Results:
Between January 2007 and July 2011 102 patients were randomized (49 SBRT, 53 3DCRT). Mean age 74 (57-86), 60% women and the vast majority (92%) had COPD or cardiovascular comorbidity. The mean FEV1 and mean CO-diffusion capacity were 1.4 L and 55% respectively. Seventy-four percent had a histopathologic diagnose where the majority were adenocarcinomas and 65% had T1 tumors and 35% T2. The two treatment groups differed somewhat in terms of tumor size and gender where the SBRT arm included more patients with T2 tumors and of male gender. The median follow-up is 37 months with a 1- 2- and 3 year PFS of: SBRT: 89%, 70%, 62% and 3DCRT: 88%, 66% 58% with no difference between the groups and no difference regarding OS. At the end of study 72% were without progression among the SBRT patients compared to 59% in the conventional arm. Toxicity was generally low, grade ≥ 3 of any toxicity was observed in 19% in SBRT patients and 15% in the 3DCRT group with no grade 5 toxicities. Pneumonitis of any grade was observed in 19% (SBRT) and 36% (3DCRT), and any grade esophagitis in 8% and 30% respectively. HRQL was evaluated with the EORTC QLQ 30 and LC14 module and patients treated with 3DCRT experienced worse dyspnea, cough and chest pain compared to the SBRT patients.
Conclusion:
NSCLC stage I patients treated with SBRT had the same PFS and OS as the conventionally treated patients despite an imbalance of prognostic factors with regards to more T2 tumors and males in the SBRT group. There was a tendency to improved disease control rate in the SBRT patients and in addition they experienced higher QoL values regarding dyspnea, cough and chest pain. SBRT should be considered standard therapy for this patient group.
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ORAL19.02 - Higher Risk of Failure and Death after Stereotactic Lung Radiotherapy for T2 Lung Cancer (ID 2945)
10:56 - 11:07 | Author(s): I. Grills, J. Belderbos, A. Hope, M. Werner-Wasik, M.D. Johnson, H. Peulen, M. Giuliani, J. Sonke, H. Ye, M. Guckenberger
- Abstract
- Presentation
Background:
Limited data are available on the use of SBRT for tumors larger than 3cm. We analyzed results from a collaborative database to compare clinical outcomes for patients with tumors > 3cm to those with smaller tumors (<3cm).
Methods:
1192 patients with 1288 T1-T3N0M0 tumors underwent cone-beam CT image-guided lung SBRT between 10/2004-12/2014. The median prescription dose was 50 Gy in 3 fractions (range 24-64 Gy in 1-10) to the PTV. Patient, tumor and treatment factors and clinical outcomes were extracted from the database. Local recurrence (LR), regional recurrence (RR), distant metastasis (DM), overall (OS) and cause-specific survival (CSS) were calculated from SBRT completion using the Kaplan-Meier method. Univariate analyses were performed using the Cox proportional hazards model. Student’s unpaired t-test and Pearson chi-square/Fisher’s Exact test were used to compare continuous and categorical variables between groups, respectively.
Results:
Mean follow-up time was 2.1y (0.02-10.12y) and similar for both groups. 295 tumors were > 3cm (T2) and 993 < 3cm (T1) (mean size 3.98 v 1.91cm (0.5-9.6cm), p<0.001). There were no statistically significant differences between groups for gender, pulmonary function (median FEV1 1.7 L (56-60% predicted); DLCO 10 ml/min/mmHg (50-51% predicted), medical inoperability (89%), PET (94%) or any invasive mediastinal staging (6%). T1 patients were slightly younger (73.5y T1 v 76.0y T2, p<0.01) and had mildly better ECOG (80% 0-1 T1 v 71% 0-1 T2, p=0.001). T2 tumors were more often biopsied (74% T2 v 63% T1, p<0.001), less often non-squamous (74% v 83%, p=0.002), had higher SUVmax (10.3 T2 v 6.4 T1, p<0.001), more often central (0236) (19% T2 v 11% T1, p=0.001) and treated to a median prescription dose of 53.8Gy T2 v 52.2Gy T1, p<0.001. 3% received chemotherapy (T1 2.6% v T2 4.4%, p=0.11). Although LR was similar between groups, large tumors had a higher risk of RR, DM and death (Table 1). On univariate analysis, LR was predicted by multiple BED parameters (p<0.001), baseline SUVmax (p=0.003) and squamous histology (p=0.012); RR was higher for lower lobe tumors (p=0.008); DM (p=0.006) was higher while OS and CSS lower for central tumors (p=0.03, 0.01).Clinical Outcome Tumor < 3 cm Tumor > 3 cm p-value Local recurrence 3y 7% 11% 0.13 5y 11% 13% Regional Recurrence 3y 9% 13% 0.006 5y 11% 24% Distant Metastasis 3y 11% 16% <0.001 5y 16% 18% Cause-Specific Survival 3y 88% 73% <0.001 5y 81% 66% Overall Survival 3y 61% 45% <0.001 5y 42% 28%
Conclusion:
Large tumors had a higher risk of RR, DM and death after SBRT. These data have implications for consideration and study of pre-SBRT invasive nodal staging and/or systemic therapy in this population. OS and CSS were lower for central tumors warranting further analysis.
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ORAL19.03 - NRG Oncology/RTOG 0813 Trial of Stereotactic Body Radiotherapy (SBRT) for Central Tumors - Adverse Events (ID 1458)
11:07 - 11:18 | Author(s): A. Bezjak, R. Paulus, L. Gaspar, R.D. Timmerman, W.L. Straube, W.F. Ryan, Y. Garces, A.T. Pu, A.K. Singh, G.M.M. Videtic, M. Suntharalingam, P. Iyengar, J.R. Pantarotto, E.A. Levine, A.Y. Sun, M.E. Daly, I. Grills, P.W. Sperduto, D.P. Normolle, J.D. Bradley, H. Choy
- Abstract
- Presentation
Background:
The safety of SBRT for medically inoperable patients with centrally located early stage non-small cell lung cancer (NSCLC) was evaluated in this phase I/II multicenter RTOG study that completed accrual in Sept 2013. This is the first report of adverse events (AE) observed on the study.
Methods:
Eligible patients were medically inoperable with biopsy proven, PET staged T1-2N0M0 NSCLC, ≤ 5 cm in size, centrally located tumors (within or touching the zone of the proximal bronchial tree or adjacent to mediastinal or pericardial pleura). Patients were successively accrued onto dose-escalating 5 fraction SBRT schedules delivered over 1.5-2 weeks, starting with 10 Gy per fraction (fr), then 10.5Gy/fr, 11 Gy/fr, 11.5 Gy/fr and 12 Gy /fr. Toxicity was graded using CTCAE v4.0; any potential dose-limiting toxicity within the initial 365 days post SBRT could have led to dose reduction for subsequent patients accrued, using TITE-CRM (time-to-event continual reassessment method) statistical design.
Results:
120 patients (100 evaluable) from 43 centers were accrued between 2/2009 and 9/2013. 12 were excluded as they did not receive protocol treatment (6 of these on the 12Gy/fr cohort) and another 8 did not meet eligibility criteria. Cohort sizes were 8 (10Gy/fr), 8 (10.5Gy/fr), 18 (11Gy/fr), 43 (11.5Gy/fr), and 43 pts (12Gy/fr). Median age was 72 (range 52- 89) years, 57% were female, 45% had squamous cell carcinoma, 39% had adenocarcinoma, 65% had T1 tumors. Median follow up was 26.6 months. Most adverse events were grade (G) 1 or 2. 5/8 pts in lowest SBRT dose cohort (10 Gy/fr) experienced G2 toxicity, none had G>3. Of 7 pts in 10.5 Gy/fr, 1 had G2 and 1 had G5 toxicity. Of 14 pts in 11 Gy/fr cohort, 4 had G2 and 1 had G3. Of 38 pts in 11.5Gy/fr cohort, 11 had G2, 4 had G3 and 2 had G5. Of 33 pts in 12Gy/fr, 4 had G2, 5 had G3, 1 G4 and 1Gr 5 as the worst overall toxicity definitely, probably or possibly related to SBRT. All Gr 5 toxicities were due to hemoptysis, occuring at a mean of 13 mo post SBRT (range 5.5-14mo). G2+ GI toxicity only occurred in the 11.5Gy/fr (1/38) and 12.0Gy/fr (2/33) cohorts. G2+ pulmonary toxicity occurred in 4/8 10.0Gy/fr, 0/8 10.5Gy/fr, 5/14 11.0Gy/fr, 15/38 11.5Gy/fr, and 10/33 12.0Gy/fr pts.
Conclusion:
This phase I/II trial of SBRT provides data to inform patients of the potential toxicities with a 5 fraction SBRT schedule for centrally located NSCLC. Although SBRT was well tolerated, 4/100 pts (4%) had fatal hemoptysis potentially attributable to SBRT. Determination of the optimal SBRT dose needs to await analysis of tumor locations, DVH data and efficacy data. This project was supported by grants U10CA21661, U10CA180868, U10CA180822 and U10CA37422 from the National Cancer Institute (NCI).
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ORAL19.04 - Discussant for ORAL19.01, ORAL19.02, ORAL19.03 (ID 3337)
11:18 - 11:28 | Author(s): F. Mornex
- Abstract
- Presentation
Abstract not provided
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ORAL19.05 - Japanese Multicenter Study of Stereotactic Body Radiotherapy for 661 Medically Operable Patients with Stage I Non-Small Cell Lung Cancer (ID 2835)
11:28 - 11:39 | Author(s): T. Komiyama, H. Onishi, Y. Shioyama, Y. Matsumoto, K. Takayama, Y. Matsuo, A. Miyakawa, H. Yamashita, K. Nihei, H. Matsushita, M. Aoki, T. Kimura, H. Ishiyama, N. Murakami, K. Nakata, A. Takeda, T. Uno, T. Nomiya
- Abstract
- Presentation
Background:
In Japan, stereotactic body radiotherapy (SBRT) has been actively used as a curative treatment option for patients with early stage primary lung cancer. We organized a multi-institutional SBRT study group in Japanese Radiological Society (JRS-SBRTSG) and conducted retrospective study of SBRT for stage I non-small cell lung cancer (NSCLC).. The purpose of this study was to evaluate the treatment outcomes of SBRT for medically operable patients with stage I NSCLC of JRS-SBRTSG.
Methods:
This is a retrospective analysis to review 661 patients (median age, 75 years; male 424, female 237) with stage I (IA 506, IB 155) NSCLC treated in 20 institutions of JRS-SBRTSG. Histology was proven in 486 patients (adenocarcinoma 328, squamous cell carcinoma 117, others 41). A total dose of 32 -70 Gy mainly at the isocenter was prescribed in 4-15fractions. The median calculated biological effective dose (BED) was 107 Gy (range, 64-150 Gy) based on alpha/beta = 10Gy)
Results:
The median follow-up period for all patients was 35 months. Pulmonary complications of NCI-CTC criteria grade > 3 and grade 5 were noted in 1.9% and 0.4% of total patients, respectively. Overall survival rate (OS) at three year (OS-3y) and disease-specific survival rate at three year of total patients was 79% and 89%, respectively. Locally progression free rate at three year was better for T1 (89%) than T2 (80%) but OS-3y was not different in the two subgroups. OS-3y of female patients was much better (93%) than for male patients (72%) (P<0.01). OS-3y was better for BED ³100 Gy subgroup (80%) than BED<100 Gy subgroup (70%). OS-3y of patients accompanying pulmonary interstitial change (n=54) was much worse (42%) than the others. According to multivariate analysis, only of male and presence of pulmonary interstitial change were worse survival factor.
Conclusion:
The outcomes of SBRT for medically operable patients with stage I NSCLC in Japanese multi-institutional large database were retrospectively analyzed. The local progression-free rate and OS were similar to those of JCOG (Japan Clinical Oncology Group) 0403; a prospective phase II study of SBRT (48 Gy in 4 fractions) for stage IA NSCLC, and the OS was almost comparable to that of surgery for high-aged patients. The subgroup of male and presence of pulmonary interstitial change were worse survival factors. SBRT might be promising as an alternative to surgery for operable stage I NSCLC
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ORAL19.06 - Tumor Location Is Associated with Recurrence Pattern and Survival after SBRT in Early Stage NSCLC Patients (ID 2623)
11:39 - 11:50 | Author(s): B. Stam, H. Peulen, J. Belderbos, M. Guckenberger, F. Mantel, I. Grills, A. Hope, N. O'Connell, J. Sonke
- Abstract
Background:
For NSCLC patients treated with SBRT, we investigated if tumor location is associated with recurrence pattern and overall survival.
Methods:
From 2006-2013 1129 patients with early stage NSCLC were treated with cone beam CT guided SBRT (median 54 Gy in 3 fractions, range 23-64 Gy in 1-10 fractions) in 5 different institutes. 719 patients were analyzed after exclusion of patients with (meta)synchronous tumors (n=185), incomplete scanning data or incomplete follow-up (n=225). An average anatomy was constructed based on 109 patients of the 5 institutes using deformable image registration[1]. Subsequently, all patients were registered to this average anatomy and the corresponding dose distribution was deformed accordingly. Tumor location was defined as a 3D Gaussian distribution (standard deviation 2 cm) at the center of the high dose region. These Gaussian distributions were added to a total and per voxel a mean and standard deviation was determined. Totals were obtained for 5 different groups: local recurrence, regional recurrence, distant metastasis, all recurrent disease combined, deceased as well as their complements. By comparing 2 complimentary groups using Welch’s t-test, locations that were significantly associated (p<0.01) with recurrent disease or with overall survival were identified. Recurrent disease rates and overall survival were calculated using the Kaplan-Meier method.
Results:
With a median follow-up of 19 months, local recurrence occurred in 5% of patients, regional recurrence in 5% and distant metastasis in 9%. 74% of patients were alive and 18% was lost to follow-up. Tumors located medially in the left upper lobe were significantly associated with controlled disease (local, regional, distant and all combined). Figure 1A displays as heatmap: disease control (green), recurrent disease (purple), and the region where the two groups differ significantly (yellow). Tumors located peripherally in the left lower lobe were significantly associated with regional recurrences. Tumors located medially/centrally in the right upper lobe were significantly associated with distant metastases and all recurrent disease combined (local, regional and distant together). Tumors located medially/centrally in the right upper lobe were significantly associated with a decreased overall survival (Figure 1B). Figure 1
Conclusion:
In this group of 719 NSCLC patients treated with SBRT, an average anatomy was utilized to analyze associations of tumor location with treatment outcome. Several regions were identified that were significantly associated with disease recurrence and overall survival. Further investigations in the underlying mechanisms of these associations are warrented. 1.ADMIRE Research 2015, Elekta AB, Stockholm, Sweden
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ORAL19.07 - A Novel Nomogram for Predicting Distant Metastases after Lung Stereotactic Body Radiotherapy for Early Stage Lung Cancer (ID 1270)
11:50 - 12:01 | Author(s): S.C. Oh, K. Chagin, N. Woody, M. Ward, Y. Pham, J. Kittel, G.M.M. Videtic, K. Stephans
- Abstract
- Presentation
Background:
While stereotactic body radiotherapy (SBRT) for early stage non-small cell lung cancer (NSCLC) results in excellent local control, distant metastases (DM) remain the most prevalent form of failure. In this analysis, we develop and internally validate a nomogram to predict DM following SBRT for NSCLC.
Methods:
We queried our institutional registry of patients treated with lung SBRT over the past decade (2003-2014) and identified 729 patients with early stage NSCLC eligible for analysis. All patients were treated with definitive intent. Initial patient and tumor variables predicting the likelihood of developing distant metastases were identified from a multivariable Cox proportional hazard model. A nomogram was developed from the initial model using 16 candidate variables and was reduced to the find the best fitting parsimonious model. The nomogram was then internally validated using a 1000 bootstrap resampling process. Accuracy of the nomogram was measured using c-statistics.
Results:
The median follow up was 15.2 months. 157 patients (22%) developed DM at a median time of 10.3 (range 0.2-68.4) months. The median time to death after development of DM was 4.5 months. Sites of DM included lung (113/157 patients), bone (36/157 patients), liver (27/157 patients), brain (25/157 patients), adrenal (8/157 patients), and other (7/157 patients). Age at start of radiotherapy (p = 0.051), tumor size (p = 0.009), PET SUV (p = 0.026), and the presence of synchronous primaries (p = 0.048) were all predictive of DM on multivariable analysis. Using seven patient and tumor variables (Age, BMI, Charlson Comorbidity Index, Tumor Size, PET SUV, Medical Operability, and Presence of a synchronous primary NSCLC), our nomogram successfully predicted distant metastasis and has an internally validated c-statistic of 0.606 (95% CI: 0.563, 0.648). Internal validation with bootstrapping demonstrated persistent validity of the nomogram in predicting distant metastases. Figure 1
Conclusion:
This novel internally validated nomogram can predict the risk of distant metastases in early stage NSCLC treated with SBRT. External validation of this nomogram is warranted. This nomogram may help define subgroups for stratification in future clinical trials and identify patients who may benefit from adjuvant systemic therapies following lung SBRT.
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ORAL19.08 - Discussant for ORAL19.05, ORAL19.06, ORAL19.07 (ID 3561)
12:01 - 12:11 | Author(s): B. Kavanagh
- Abstract
- Presentation
Abstract not provided
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Author of
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MINI 01 - Pathology (ID 93)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:W.A. Franklin, A.G. Nicholson
- Coordinates: 9/07/2015, 10:45 - 12:15, Mile High Ballroom 2c-3c
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MINI01.11 - Transcriptome Sequencing of Tumor vs. Surrounding Non-Malignant Lung Tissue in Non-Small Cell Lung Cancer (ID 1765)
11:45 - 11:50 | Author(s): D. De Ruysscher
- Abstract
Background:
Both the response and the therapeutic ratio of targeted agents in NSCLC may depend on the expression of the target molecules in the tumor and the surrounding non-malignant lung tissue. We therefore performed transcriptome analysis and investigated correlations with histology, gender, age, CRP level and smoking status as well as evaluated the differential pathway expression in primary resected NSCLC and the surrounding non-malignant lung of the same patient.
Methods:
Transcriptome sequencing was performed on the primary tumor and distant lung tissue of the same patient from resection specimens of NSCLC patients. Differential gene expression between different conditions was identified using the statistical algorithms Cufflinks, EdgeR and DeSeq. Differential expression with P-values <0.05 after Benjamini-Hochberg correction was considered significant. Pathway analysis for overall tumor versus distant lung tissue was performed with the PANTHER gene classification platform using the Cufflinks, DeSeq and EdgeR differentially expressed gene sets as input.
Results:
Twenty-five patients were studied, 19 males and 6 females, with a median age of 69 years. Ten were current smokers, 14 former smokers (>4 weeks before surgery) and 1 non-smoker. Eleven patients had squamous cell carcinoma, 14 adenocarcinoma. A heat map with the results for the most commonly targeted genes in NSCLC is represented in figure 1. When compared to distant lung tissue, PD-L1 was downregulated in tumor tissue of adenocarcinoma and active smokers, but not in squamous cell carcinoma or ex-smokers. Internal control of tumor tissue of squamous vs. adenocarcinoma and ex-smokers vs. active smokers shows an important trend towards a higher expression of PD-L1 in squamous cell carcinoma and ex-smokers in both Cufflinks and EdgeR algorithms. Additional pathway analysis revealed 188 differentially regulated pathways. The most notable were downregulation of VEGF signaling, angiogenesis and B and T cell activation in tumor tissue when compared to distant lung tissue. Figure 1
Conclusion:
Our first results show a higher expression of PD-L1 in squamous tumors than in adenocarcinoma and a higher expression in tumors of ex-smokers than in those of active smokers. This may have consequences for the therapeutic ratio with anti-PD-L1 treatment. Downregulation of VEGFR-genes in tumor tissue was observed across almost all conditions. We will make this data more complete by adding methylation data as well as immunohistochemistry for protein localization.
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MINI 25 - Trials, Radiation and Other (ID 142)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:J.M. Clavero, R. Hassan
- Coordinates: 9/08/2015, 16:45 - 18:15, 702+704+706
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MINI25.11 - Optimization of Gross Tumour Volume Definition in Lung-Sparing Volumetric Modulated Arc Therapy for Pleural Mesothelioma (ID 2860)
17:45 - 17:50 | Author(s): D. De Ruysscher
- Abstract
- Presentation
Background:
High dose lung-sparing pleural radiotherapy for malignant pleural mesothelioma (MPM) is difficult. Given the steep dose gradient with volumetric modulated arc therapy (VMAT), accurate target delineation is critical. The optimal imaging modality to define radiotherapy target volumes has not been studied in depth. This is the aim of the present study.
Methods:
Twelve consecutive patients with a histopathological diagnosis of stage I-IV MPM (6 left-sided and 6 right-sided) were included. CT scans with intravenous (IV) contrast, [18]F-FDG PET/CT scans, MRI scans (post-contrast T1-weighted and T2-weighted) and diffusion-weighted images (DWI) were obtained and downloaded from the institutional database onto a standalone image fusion workstation (MIM Software Inc., Cleveland, OH, USA) for image registration and contouring. CT scans were rigidly co-registered with ~18~FDG-CT-PET, with MRI scans and with DWI scans. Four sets of pleural GTVs were defined: 1) a CT-based GTV (GTV~CT~); 2) a PET/CT-based GTV (GTV~CT+PET/CT~); 3) a T1/T2-weighted MRI-based GTV (GTV~CT+MRI~); 4) a DWI-based GTV (GTV~CT+DWI~). Only the pleural tumor was contoured; mediastinal nodes were excluded. In each of the 4 co-registrations, a “quantitative” and a “qualitative” (visual) evaluation of the volumes were performed. “Quantitative” evaluation was carried out through the coefficient of variation (COV; the ratio between the standard deviation [SD] and the mean: a measure of the dispersion of a distribution) and the Jaccard index (the ratio between the union and the intersection between two volumes: a measure of overlap). “Qualitative” evaluation consisted of a visual identification of any additional tumor site in each of the 4 obtained co-registrations.
Results:
Compared to CT-based GTV definition, PET/CT identified additional tumour sites in 12/16 patients. Compared to either CT or PET/CT, MRI and DWI identified additional tumour sites in 15/16 patients. Additional tumour sites were mainly the parietal pleura, the diaphragm and the chest wall. Mean GTV~CT~, GTV~CT+PET/CT~, GTV~CT+MRI~ and GTV~CT+DWI~ (+SD) were respectively 630.1 mL (+302.81), 640.23 (+302.83), 660.8 (+290.8) and 655.2 mL (+290.7). Mean Jaccard index was lower in MRI-based contours versus all the others.
Conclusion:
To the best of our knowledge, this is the first study showing that the integration of the MRI (T1/T2-weighted) and DWI into the target volume definition in lung-sparing hemi-thoracic VMAT in MPM may allow to improve the accuracy of target delineation and reduce the likelihood of geographical misses.
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MINI 33 - Radiotherapy and Complications (ID 164)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Locoregional Disease – NSCLC
- Presentations: 1
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MINI33.10 - Discussant for MINI33.06, MINI33.07, MINI33.08, MINI33.09 (ID 3476)
19:25 - 19:35 | Author(s): D. De Ruysscher
- Abstract
- Presentation
Abstract not provided
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MINI 37 - SCLC Therapy (ID 165)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Small Cell Lung Cancer
- Presentations: 1
- Moderators:D. Ettinger, G.R. Simon
- Coordinates: 9/09/2015, 18:30 - 20:00, 605+607
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MINI37.11 - Inter-Observer Variability in Hippocampus Delineation on MRI Scans for Hippocampal Avoidance Prophylactic Cranial Irradiation Trial (ID 2620)
19:30 - 19:35 | Author(s): D. De Ruysscher
- Abstract
- Presentation
Background:
Prophylactic cranial irradiation (PCI) is the standard treatment in patients with small-cell lung cancer (SCLC) without progression after chemo-radiotherapy in stage I-III disease and after having a remission after chemotherapy in stage IV. In an international phase III trial (NCT01780675), patients with SCLC are randomised to receive PCI with or without Hippocampal Avoidance (HA). Accurate delineation of the hippocampus is crucial for this trial. In this study we evaluate the hippocampus delineation variability among radiation oncologists in multi-institutions for SCLC patients.
Methods:
The left and right hippocampus from 5 randomly selected patients (10 structures) were delineated by 5 radiation oncologists and 2 neuroradiologist in 7 institutions according to the RTOG atlas (http://www.rtog.org/CoreLab/ContouringAtlases/HippocampalSparing.aspx), together with a questionnaire. For each patient, a high resolution 3D inversion recovery T1 weighted MRI-scan was first registered to the planning CT-scan (1mm slicing). The observer then delineated the hippocampus according to the atlas on axial slices of the MRI. The mapped delineations on the CT were then used in dose planning with a 5mm margin. The mean and standard deviation (SD) of 1) volume and 2) range in medio-lateral, superior-inferior and anterior-posterior directions were computed for each structure. The corresponding inter-observer reliability was estimated by the intra-class correlation coefficient (ICC absolute agreement) using a linear mixed model. A median surface was computed and the overall delineation variability per structure was calculated by the root-mean-square (rms) of the local SD per sampled points on the median surface, while the local SD corresponds to the perpendicular distance between each observer and a sampled point.
Results:
The standard deviation of the delineated volume per structure varied from 0.14 to 0.48cm3. The corresponding inter-observer reliability (ICC) was 0.19, implying a high variability among the observers. The overall delineation variability per structure varied from 0.6 to 1.0mm. Areas with good agreements were the superior and inferior part of the hippocampus. The difficult area (Fig.1) was in the anterior medial area, close to the amygdala and uncus. The ICC in medio-lateral, superior-inferior and anterior-posterior directions were 0.55, 0.64 and 0.80, respectively. A large spread of the SD of range in medio-lateral direction and the relative low ICC imply that a better instruction, or training is desirable to improve the delineations. Figure 1
Conclusion:
There was a substantial variability in hippocampus delineation among the observers. Stricter adherence to the RTOG guidelines and (web-based) training are needed. The implication of the variations on the dose distribution is currently verified.
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ORAL 36 - Translational Science/Radiation (ID 151)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Locoregional Disease – NSCLC
- Presentations: 1
- Moderators:E. Vokes, B. Kavanagh
- Coordinates: 9/09/2015, 16:45 - 18:15, Mile High Ballroom 2c-3c
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ORAL36.04 - Nintedanib Safely Reduces Late Radiation-Induced Lung Damage: A Preclinical Study with a High Precision Image-Guided Small Animal Irradiator (ID 1456)
17:17 - 17:28 | Author(s): D. De Ruysscher
- Abstract
- Presentation
Background:
The indolinone small-molecule derivative nintedanib has been originally designed as an anti-angiogenic drug targeting the receptor tyrosine kinases VEGFR, FGFR and PDGFR for the treatment of cancer. Additionally, preclinically nintedanib has demonstrated potent anti-fibrotic and anti-inflammatory activity. Nintedanib was recently approved in the US and EU for the treatment of idiopathic pulmonary fibrosis (IPF). The aim of this study was to assess the efficacy and safety of nintedanib in a mouse model of partial lung irradiation.
Methods:
266 C57BL/6 adult male mice were irradiated with a single fraction radiation dose of 0, 4, 8, 12, 16 or 20 Gy using 5-mm circular parallel-opposed fields targeting the upper right lung with a precision image-guided small animal irradiator (PXRAD225Cx, PXI Inc, USA) sparing heart and spine based on micro-CT images acquired at 200 µm resolution. One week post irradiation, mice were randomized across nintedanib daily oral gavage treatment with 0, 30 or 60 mg/kg respectively for a total of 39 weeks. Micro-CT imaging was repeated on a monthly basis. At the end of the experiment, lungs were removed and processed for H&E, Van Gieson’s and Masson’s trichrome staining to evaluate the fibrotic phenotype.
Results:
Increased lung density could be visually observed by CT in the late stage imaging time points of irradiated mice after 20 Gy and was spatially limited to the irradiated portion of the lung. This increased density was consistent with the development of fibrosis, confirmed by an increased fibrotic phenotype scored by an increase in alveolar wall thickness, interstitial edema, interstitial and perivascular fibrosis and inflammation, interstitial and alveolar macrophages, atelectasis and vasculitis. Although no macroscopic decrease in CT density could be observed, nintedanib was able to reduce the microscopic fibrotic phenotype, in particular interstitial edema, interstitial and perivascular fibrosis and inflammation and vasculitis, without adverse effects.
Conclusion:
Nintedanib efficiently and safely reduces radiation-induced lung fibrosis after partial lung irradiation. Since, as expected, nintedanib did not affect alveolar wall thickness and macrophage involvement, no significant changes in lung density could be observed by CT imaging. Based on its protective effect, nintedanib might be safely introduced in clinical trials for patients treated with irradiation to the lungs.
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P1.03 - Poster Session/ Treatment of Locoregional Disease – NSCLC (ID 212)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Locoregional Disease – NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.03-021 - Lung Damage Quantification on CT Scans Strengthens Radiation-Induced Lung Toxicity Prediction Models (ID 2932)
09:30 - 09:30 | Author(s): D. De Ruysscher
- Abstract
Background:
Predictive models for radiation-induced lung toxicity have shown a lack of validation and low values of area under the curve (AUC) below 0.7, for various reasons. Radiation-induced lung tissue damage scored as density changes on CT scans proved to be a less multifactorial endpoint compared to dyspnea. Its continuous variation in the patient population is an indication that it could be an expression of patient-specific radiosensitivity variation. This study explores the advantage of incorporating patient-specific lung damage measures in the classical predictive models based on mean lung dose (MLD).
Methods:
61 stage I-IV lung cancer patients treated with chemoradiotherapy were retrieved from two hospitals. Prescribed dose was 66 Gy in fractions of 2 Gy (concurrent) or 2.75 Gy (sequential). Baseline and follow-up dyspnea scores were retrospectively assessed according to CTCAE 4.0. Image analysis of the radiation-induced lung damage was performed by comparison of the baseline planning CT~0~ and the non-rigidly registered follow-up CT~fup~. The median Hounsfield Unit increase (∆HU=HU~fup~-HU~0~) was calculated per dose bin of 5 Gy. The local dose-∆HU response curve was described using a sigmoidal model. This resulted in a sigmoidal parameter D~50~ (corresponding to 50% of the saturation level of ∆HU) for each patient, as an expression of the patient-specific lung tissue radiosensitivity. Logistic models predicting dyspnea increase with respect to the baseline score were then built using MLD and D~50~ as covariates. The likelihood-ratio identified significant differences between nested models.
Results:
Dyspnea score increase by 2 grades was observed in 9 patients (14,8%), while an increase by 1 grade was observed in 29 patients (47.5%). The average timepoint of CT~fup~ was 2.3 months after end of radiotherapy. For 51 patients the sigmoidal dose-∆HU fits were acceptable (sum of squared residuals below 10 HU per datapoint on average). 10 of these patients did not show any dose response in the analysed dose range. The 41 reacting patients showed large variation in D~50 ~(median: 34.8 Gy, range: 12.1 Gy-70.0 Gy) and were further analysed. Predictive models based on MLD alone had AUCs of 0.71 and 0.65 for dyspnea increase by 1 and 2 grades respectively. Incorporating the CT damage measure D~50~ as second covariate resulted in models with 0.73 and 0.83 respectively. The advantage of incorporating D~50~ was significant in the second fit (p=0.05).
Conclusion:
A significant improvement of predictive models for radiation-induced lung toxicity was achieved using patient-specific lung damage measured on CT scans. An early detection of the patient-specific D~50~ through dedicated per-treatment imaging optimized for the detection of lung tissue changes is crucial for the clinical implementation of the model. Future work analysing more CT features could also improve the model.
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P1.08 - Poster Session/ Thymoma, Mesothelioma and Other Thoracic Malignancies (ID 224)
- Event: WCLC 2015
- Type: Poster
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.08-006 - Lung Toxicity after Post-Operative Radiotherapy after EPP for Mesothelioma and Pneumonectomy for Non-Small Cell Lung Cancer (ID 2863)
09:30 - 09:30 | Author(s): D. De Ruysscher
- Abstract
Background:
Our hypothesis is that MPM patients treated with post-operative RT after EPP are more prone to develop lung toxicity compared to non-small cell lung cancer (NCSLC) patients treated with post-operative RT after pneumonectomy, since their higher baseline inflammation status.
Methods:
We retrospectively reviewed the records of 39 consecutive patients with MPM who received post-operative RT after extrapleural pneumonectomy (EPP), and of 10 consecutive patients with non-small cell lung cancer who received post-operative RT after pneumonectomy between March 2003 and March 2012 at the University Hospitals of Leuven. For MPM patients, the planning target volume was defined as the entire hemi-thorax, chest wall incisions, drain sites, and involved nodal stations. Prescription dose was 54 Gy in 2-Gy fractions delivered to the planning target volume (PTV). For NSCLC patients, the planning target volume was defined as mediastinal nodal stations according to the pathologic nodal involvement. Prescription dose was 54-66 Gy in 2-Gy fractions delivered to the PTV. Both cohorts received induction systemic chemotherapy before surgery. Primary endpoint was lung toxicity. Dyspnea was graded using the Common Toxicity Criteria (CTC) v. 4.03 and was recorded before RT, 45 days after the completion of RT and every 3 months thereafter until the completion of the follow up. Dosimetric dose-volume parameters (lung V5, lung V20, mean lung dose [MLD], mean heart dose, heart V45) were retrieved for both cohorts. The correlation between the dosimetric parameters and the toxicity (dyspnea score) was investigated.
Results:
In MPM patients, the dyspnea score was 0-1 in 24/39 patients (61.5%), 2 in 11/39 patients (28.2%), 3 in 3/39 patients (7.7%) and 4 in 1/39 patients (2.5%). No grade 5 toxicity was recorded. In NSCLC patients, only grade 0-1 dyspnea was registered (grade 0: 4/10 patients; grade 1: 6/10 patients). Mean MLD was 7.56 Gy (range: 1.60-14.80; SD: 3.65) for the MPM group and 5.96 Gy (range: 3.2-14.5; SD: 3.57) for the NSCLC group. Univariate analysis showed a significant correlation between grade > 2 dyspnea and MLD, lung V5 and lung V20.
Conclusion:
Post-operative radiotherapy after EPP is well-tolerated, with 10% of patients experiencing grade > 3 dyspnea. Strict dose-constraints should be applied when radiotherapy is administered in multimodality treatment.
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P2.03 - Poster Session/ Treatment of Locoregional Disease – NSCLC (ID 213)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Locoregional Disease – NSCLC
- Presentations: 2
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.03-022 - Is the Radiosensitivity of the Tumour Related to That of the Lung? A CT-Based Response Analysis of Both (ID 2829)
09:30 - 09:30 | Author(s): D. De Ruysscher
- Abstract
Background:
Lung tissue damage after radiotherapy scored as density changes on CT scans proved to be a less multifactorial endpoint compared to dyspnea. Its continuous variation in the patient population is an indication that it could be an expression of patient-specific radiosensitivity variation. This study linked patients’ lung damage measures defined on CT with tumour shrinkage.
Methods:
32 stage I-IV lung cancer patients treated with chemoradiotherapy were studied. Prescribed dose was 66 Gy in fractions of 2 Gy (concurrent) or 2.75 Gy (sequential). Image analysis of the radiation-induced lung damage was performed by comparison of the baseline planning CT~0~ and the non-rigidly registered follow-up CT~fup~. The median Hounsfield Unit increase (∆HU=HU~fup~-HU~0~) was calculated per dose bin of 5 Gy. The local dose-∆HU response curve was described using a sigmoidal model. This resulted in a sigmoidal parameter D~50~ (corresponding to 50% of the saturation level of ∆HU) for each patient, as an expression of the patient-specific lung tissue radiosensitivity. On both the CT~0~ and CT~fup~ scans, an experienced radiation oncologist delineated the tumour gross target volume (GTV). Volumetric (volume and equivalent diameter) and intensity-based (median, maximal and minimal HU) features were collected for all GTVs.
Results:
The average timepoint of CT~fup~ was 2.3 months after end of radiotherapy. For 25 patients the sigmoidal dose-∆HU fits were acceptable (sum of squared residuals below 10 HU per datapoint on average). 8 of these patients did not show any dose response in the analysed dose range. The 17 reacting patients showed large variation in D~50 ~(median: 30.9 Gy, range: 15,8 Gy-70,0 Gy) and were further analysed. Their median GTV volumes were 25.9cc (range 1.3cc-275.9cc) and 5.2cc (range 0.4cc-42.4cc) on CT~0~ and CT~fup ~respectively~.~ No correlation of tumour intensity-based features with lung D~50~ was observed. The relative diameter change of tumour however showed moderate correlation (R[2]=0.21) with lung radiosensitivity (see Figure). Patients with D~50~ below the population’s median showed a mean reduction of tumour diameter of 46.8%, while this was 30.0% in the group with high D~50 ~(p=0.03).Figure 1
Conclusion:
The patient-specific D~50~ for lung damage shows correlation with tumour shrinkage. This corroborates the hypothesis that it is a measure of intrinsic radiosensitivity. This study shows that imaging characteristics can provide independent and reproducible measures of radiosensitivity and can play a crucial role in defining patient-specific therapeutic ratio and thus treatment selection. Future radiogenomics studies could also benefit from the input of imaging.
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P2.03-023 - In-Field Nodal Relapse after Irradiation for Locally Advanced Non-Small-Cell Lung Cancer: Is There a Dose-Effect Relationship? (ID 3201)
09:30 - 09:30 | Author(s): D. De Ruysscher
- Abstract
Background:
We investigated whether prescribed radiation dose is related to in-field nodal relapse. Since in-field nodal relapse is rare according to current literature, the influence of radiation dose on the incidence could be questioned.
Methods:
A retrospective analysis of prospective data was performed. Pathologic lymph nodes were registered based on RECIST 1.1 criteria. An in-field nodal relapse is defined as an increase of at least 20% of the short axis diameter and a minimum absolute increase of 2 mm, taking as reference the short axis diameter measured 3 months (+/-2 months) after radiation therapy. Three subgroups were defined based on EQD2,T (group A: EQD2,T < 50 Gy, group B: EQD2,T 50-55 Gy, group C: EQD2,T > 55 Gy). An actuarial Kaplan-Meier analysis was performed to evaluate the cumulative proportion of in-field nodal relapse per subgroup. A Cox proportional hazards regression analysis was performed to take initial nodal diameter into account.
Results:
A total of 75 patients were reviewed. Sixty-two patients (83%) had stadium IIIA/IIIB disease. Twelve patients (16%) had stadium IV NSCLC who were treated with a radical oligometastatic approach. One patient (1%) had stadium IIB disease. Sixteen patients (21%) were treated with radiotherapy alone (38% group A, 25% group B, 38% group C). Sequential chemoradiotherapy was given in 47 patients (63%) (32% group A, 45% group B and 23% group C). Twelve patients (16%) received concurrent chemoradiotherapy (33% group A, 66% group B). Group A consisted of 25 patients (median age: 65 years (range 45-88), median follow-up: 6 months (range 1-54)). Thirty-three patients were included in group B (median age: 59 years (range 45-80), median follow-up: 8 months (range 1-86)). Group C consisted of seventeen patients (median age: 67 years (range 54-83), median follow-up: 9 months (range 2-45)). In all three groups median number of follow-up CT scans is 2 (range of 1-11 for group A and C, range of 1-13 for group B). Any relapse occurred in fifty-eight patients (77,3%). Nineteen patients (33%) had a locoregional failure only. Twenty-two patients (38%) had distant failure only, either by progression of a known metastasis or occurrence of a new distant lesion. Seventeen patients (29%) had a locoregional and distant failure at once. A total of 142 lymph nodes were taken into account (55 (39%) in group A, 52 (37%) in group B and 35 (25%) in group C). The average baseline short axis diameter per group was 16,3 mm, 15,8 mm and 14,6 mm for group A, B and C respectively. An actuarial Kaplan-Meier analysis performed on all lymph nodes (n=142) showed no significant difference between subgroups (p=0,24). A Cox proportional hazards regression analysis didn’t show a significant effect of baseline nodal diameter on in-field nodal relapse (p=0,82).
Conclusion:
Prescribed radiation dose is not related to the occurrence of in-field nodal relapse. There was no relation between initial lymph node diameter and in-field nodal relapse.
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P3.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 235)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.04-086 - REQUITE: Validating Predictive Models and Biomarkers of RT Toxicity to Reduce Side Effects and Improve QOL (ID 2864)
09:30 - 09:30 | Author(s): D. De Ruysscher
- Abstract
Background:
Recently the first replicated genetic associations for radiotherapy-induced adverse reactions were reported. These should improve the power of toxicity prediction models, opening the way to an optimised radiotherapy delivery and interventions to alleviate the side effects. The European Union funded REQUITE consortium aims to validate known predictors of adverse reactions and to develop statistical models resulting in clinically useful models. The focus of the project is on breast, prostate and lung cancer. As the barrier to clinical impact is the lack of validated statistical models incorporating genetic predictors, and the barrier to validation is the lack of standardised data collection, the main objectives of the REQUITE project are the following: Perform a multi-centre cohort study collecting blood samples, epidemiology and treatment data, longitudinal side effect and quality of life (QOL) data (before and after treatment: years 1 and 2 for breast and prostate cancer; with additional 3 and 6 month timepoints for lung cancer). Produce a centralized database and biobank of DNA for 5300 patients. Validate published biomarkers of radiosensitivity. Validate clinical predictors of radiotherapy toxicity in breast, prostate and lung cancer and incorporate biomarker data. Design interventional trials to reduce long-term side effects. Provide a resource for dissemination and exploitation to the radiotherapy community.
Methods:
The central activity of the project is a multi-centre, observational study organized through WP2. Enrolment will proceed for two years in nine centres (eight in Europe and one in the United States), with another two years of follow-up. The primary endpoints are change in breast appearance at two years (breast), rectal bleeding at two years (prostate) and pneumonitis at 6 months (lung). An integrated study database is designed. Blood samples are collected before radiotherapy. Tracking, biobanking and DNA extraction is handled in WP3. Validation of biomarkers (genetic markers and apoptosis assays) as predictive factors is carried out in WP4. Some clinical factors have suggested predictive value for radiotherapy side effects, but there is no consensus. In WP5 these will be validated in existing cohorts. Finally, in WP6, predictive models will be used to design clinical interventional trials and produce protocols that seek to lower radiotherapy side effects, in those individuals at high risk of developing them, without affecting tumour control. Patient advocates will play an essential role in this effort.
Results:
Standardised data collection forms were generated. Questionnaires for collecting patient reported toxicity according to Common Toxicity Criteria for Adverse Events were developed in different languages. These forms and questionnaires are available at http://www.requite.eu/. A centralised database for electronic data capture and storage was developed. Ethical approval for the observational study was obtained in all centres. More than 1300 patients were enrolled in the REQUITE study to this date.
Conclusion:
Centralised collection of standardised data and biobanking is practical for lung cancer patients undergoing radiotherapy in routine clinical practice in a multi-centre, multi-national setting.
