Virtual Library

 x 
My Library Virtual Library FAQ

Start Your Search

J.J. Sonke



Author of

  • +

    MO17 - Radiotherapy I: Stereotactic Ablative Body Radiotherapy (ID 106)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Radiation Oncology + Radiotherapy
    • Presentations: 2
    • +

      MO17.05 - Recurrence, Survival, and Toxicity after Stereotactic Lung Radiotherapy (SBRT) for Central versus Peripheral Stage I Non-Small Cell Lung Cancer (NSCLC): Results from an International Collaborative Research Group (ID 3436)

      16:35 - 16:40  |  Author(s): J.J. Sonke

      • Abstract
      • Presentation
      • Slides

      Background
      SBRT is an accepted safe and effective treatment modality for peripheral (P) stage I NSCLC tumors. Concern of excessive toxicity, however, limits its use for central (C) tumors. This study evaluates outcomes and toxicities after cone-beam CT (CBCT) image-guided SBRT for central vs. peripheral NSCLC.

      Methods
      959 lung tumors were treated with lung SBRT from 1998-2012 at five international centers participating in the Elekta Collaborative Lung Research Group; 98% underwent online CBCT IGRT. 100 cases were classified as Central (C) and 869 Peripheral (P), defined as ≤2cm vs. >2cm from the proximal bronchial tree, respectively. Staging included chest CT and routine chemistry for all; 93% had PET staging (mean time PET to SBRT 6.4 weeks); 6% had mediastinal sampling (mediastinoscopy or endobronchial ultrasound). 61% had tumor biopsy (84% C vs. 59% P, p<0.001). 89% were medically inoperable with mean baseline FEV1 of 1.6L (63% of predicted) and mean baseline DLCO of 12.1 ml/min/mmHg (56% of predicted). Mean age was 74y (42-93) with a large range in ECOG performance status (27%; 47%; 23%; 26% for 0-3, respectively). Clinical stage was T1aN0 44%, T1bN0 30%, T2aN0 23%, T2bN0 32%. Mean tumor maximum dimension was 2.5cm (range 0.5-8.5cm); C tumors were larger (mean 3.lcm vs. 2.4 cm, p<0.001). Mean SBRT prescription dose was 51.5±6.4 Gy, with mean dose per fraction of 14.5±4.0 Gy in 3.9±1.5 fractions. Mean biological equivalent dose (BED) was 126.6±26.6 Gy, higher for P vs. C tumors (129.2 vs. 104.0 Gy, p<0.001. Chemotherapy was administered more for C (9%) than P tumors (2%), p<0.001. Groups were compared with t-test & chi-square. Competing risks analyses were used, accounting for the competing risk of death.

      Results
      Mean follow-up for all cases was 1.8y (0.1-7.7y; mean potential follow-up 3.4y), similar for C&P. C tumors had higher Local Failure (LF) (3y-LF 16.2%C vs. 5.9%P; 5y-LF 20.4%C vs. 8.3%P, p<0.001), similar regional nodal recurrences (RR) (3y-RR 12%C vs.12%P, p=0.69) and distant metastases (DM) (3y-DM 19%C vs 20%P, p=0.75), lower cause-specific survival (CSS) (3yr-CSS 75%C vs. 88%P, p<0.001), but similar overall survival (OS) (3y-OS 50%C vs. 51%P, p=0.70). Grade > 2 pneumonitis was higher for C tumors (8%C vs. 1%P, p<0.001). Incidence of grade 3 pneumonitis, chest wall pain/myositis, rib fracture, and skin dermatitis were rare (0.8%, 0.5%, 0.4%, 0.6% respectively for all) with no differences between C&P. No grade 4 toxicities were noted, though 2 cases (1C & 1P) of fatal pneumonitis were potentially attributable to SBRT. On multivariate analysis, BED (HR:0.975, p<0.001) predicted CSS, and both BED (HR:0.978, p=0.002) and baseline SUVmax (HR:1.04, p=0.001) predicted LF. Weeks from PET-staging until SBRT (HR:1.25, p=0.004) and the percent of lungs receiving >20 Gy (HR:1.063, p=0.001) were the strongest independent predictors of OS.

      Conclusion
      In this large data set, pneumonitis was higher for central tumors, but both central & peripheral SBRT were safe with similar overall and cause-specific survival. LF was higher for central tumors, which were larger, had higher baseline SUVmax, and received lower dose. Results of the ongoing RTOG 0813 dose-finding study for central tumors are awaited.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

    • +

      MO17.08 - TCP modeling in Stereotactic Body Radiotherapy for early stage non small cell lung cancer: is a dose-volume effect present? (ID 2205)

      17:00 - 17:05  |  Author(s): J.J. Sonke

      • Abstract
      • Presentation
      • Slides

      Background
      In early stage non-small cell lung cancer (NSCLC) stereotactic body radiotherapy (SBRT) has become standard of care for inoperable patients. Tumor size >3cm was reported to be a predictor of local recurrence (LR), suggesting a dose-volume effect. Recently, the dose effect relation was questioned[1]. We used a Tumor-Control-Probability (TCP) model on a large pooled multi-center cohort to test this.

      Methods
      850 patients were analyzed from our five institutes. Patients received a 4D CT-scan and plans were inversely optimized using advanced dose calculation algorithms. Treatment was delivered using online cone-beam CT guidance. Immobilization, margins, dose prescription and treatment planning was performed according to institute specific protocols. Median tumor diameter was 2.2 cm (range:0.7-8.0), median prescribed dose was 54 Gy (range:18-64) and median number of fractions were 3 (range:1-10). LRs were either biopsy proven or defined as a FDG-PET positive growing mass on CT-scan. The Web-Nahum TCP-model[2] was fitted to LR-data using maximum-likelihood estimation by optimizing its parameters: α representing the population-average radio-sensitivity, σ~α~ representing the population-variation in α and ρ the clonogen density. Input variables were the patient specific Gross Tumor Volume (estimated from the tumor diameter), for the dosimetric parameter PTV-D~min~, D~max~, D~mean~, D~1~, D~99~ were evaluated after conversion to Biological-Effective-Dose (BED) using the LQ-model with α/β=10Gy. We tested the optimized TCP model against a random model in which TCP was fixed independent of dose and volume. The optimal model was selected based on the Akaike-Information-Criterion (AIC).

      Results
      After a median follow up (FU) of 17 months (range:0-93), 43 LRs (5%) were diagnosed at 14 months FU (range:2-56), of which 25 tumors were biopsy proven and 18 recurrences diagnosed on PET-CT. The PTV-BED~mean~ based TCP model showed the best fit with parameters α=0.43Gy[-1] (CI:0.33–0.75) and σ~α~=0.17 Gy[-1] (CI:0.11–0.37). The model-fit was insensitive to ρ and set to literature values: 10[7]/cm[3]. The AIC of the optimal model was 12 units higher than the random model indicating a clear dose-volume-effect. At high PTV~mean~-BEDs, however, the volume effect is modest. Additionally, the AIC of the BED corrected model was 9.4 units higher than the BED uncorrected model. Figure 1

      Conclusion
      A dose-volume-effect relation in SBRT for early stage NSCLC for local control was derived in a large cohort of patients. This dose-effect relation requires validation in independent datasets and prospective trials. 1.van Baardwijk,Rad.Onc.,2012. 2.Web&Nahum,PMB,1993.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

  • +

    O10 - Stereotactic Ablative Body Radiotherapy (ID 104)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Radiation Oncology + Radiotherapy
    • Presentations: 1
    • +

      O10.07 - Dose-response analysis of radiation induced rib fractures after SBRT for NSCLC (ID 2690)

      17:20 - 17:30  |  Author(s): J.J. Sonke

      • Abstract
      • Presentation
      • Slides

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

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

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

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

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

  • +

    O14 - Radiotherapy - Toxicity and Clinical Trials (ID 105)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Radiation Oncology + Radiotherapy
    • Presentations: 1
    • +

      O14.02 - Vertebral fractures in NSCLC patients treated with IMRT and concurrent chemotherapy (ID 1880)

      10:40 - 10:50  |  Author(s): J.J. Sonke

      • Abstract
      • Presentation
      • Slides

      Background
      Purpose To report on the incidence of vertebral fractures in locally advanced NSCLC patients treated with intensity modulated radiation therapy (IMRT) and concurrent chemotherapy. The RT dose to the vertebra was analyzed for its association with fractures.

      Methods
      Methods A total of 524 patients were treated between 2007 and 2011, with hypofractionated IMRT (66Gy/24fx) and concurrent daily low dose cisplatin. Planning and follow-up CT or MRI scans were retrospectively utilized to identify vertebral collapse by an experienced radiologist and a technician. Clinical and dosimetric parameters were retrospectively collected. Patients were excluded if they had no follow-up CT/MRI scan; had prior irradiation for thoracic or head and neck cancer; showed a vertebral fracture in the planning CT; or had vertebral collapse due to other causes. First, we reported the incidence of vertebral fractures. Afterwards, we analyzed the RT dose effect relationship using the maximum (Dmax) and mean (Dmean) dose to each vertebra. Dose-response was modeled using Cox model with patient as random effect. Data were analyzed using R, package “coxme”.

      Results
      Results Three hundred and thirty six patients were eligible for analysis. The median follow-up was 24 months The median age was 64 years (range 32-87); 40% of the patients female and 94% had a performance score (PS) 0-1. Twenty-eight (8%) patients developed ≥ 1 vertebral fracture; 22 had 1 vertebral fracture, 5 had 2 and 1 patient had 3 vertebral fractures. All fractures were located from the 6[th]-8[th] thoracic vertebra.The median onset time for the fracture was 7 months (range 2-26). The median age for the 28 fractured patients was 70 years (range 42-82); 61% were female, 89% had a PS of 0-1. The median Dmax was 40Gy (range 0-83) and 72Gy (range 42-83) for non-collapsed and fractured vertebrae, respectively. The median Dmean was 12Gy (range 0-65) and 51Gy (range 18-71) for non-collapsed and collapsed vertebras, respectively. Both Dmax and Dmean were significantly (p<0.001) associated with vertebral fractures.

      Conclusion
      Conclusion Vertebral fractures were retrospectively identified in 8% of NSCLC patients treated with IMRT and concurrent chemotherapy. The median onset time was 7 months. Both Dmax and Dmean of the vertebra were significantly associated with collapse in the collapsed population. A case-control study is in progress to analyze the dose-response relationship in the entire population and incorporate clinical variables, such as age, performance status and menopause status.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

  • +

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

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Radiation Oncology + Radiotherapy
    • Presentations: 1
    • +

      P2.08-020 - Prognositc parameters for local and regional control in locally advanced NSCLC patients treated with concurrent chemo-radiotherapy (ID 2385)

      09:30 - 09:30  |  Author(s): J.J. Sonke

      • Abstract

      Background
      Traditionally, the same radiotherapy dose is prescribed to the primary tumor (PT) and involved lymph nodes (LN) for locally advanced NSCLC patients, independent of volume and metabolic activity of each lesion. On the other hand, the PT and lesions with a high [18]F-FDG uptake are often believed to have a higher recurrence rate. The purpose of this study was therefore to find prognostic parameters for the lesion control probability in locally advanced NSCLC.

      Methods
      A total of 279 patients treated between 2007 and 2011 with 24×2.75Gy IMRT and concurrent daily low dose cisplatin were included in this retrospective analysis. Patients had a staging FDG-PET scan within 6 weeks prior the start of treatment. For follow-up, CT thorax was performed 4-6 weeks after treatment and at 3-monthly intervals chest x-ray or CT scans were made up to 2 years after CCRT. Medical records of the patients were retrospectively reviewed. The PT and/or LN progression were classified based on follow-up records and scans by two physicians. The volume of each separate lesion on the planning CT and their SUVmax from the pre-RT staging PET scan were then tested as prognostic factors for disease progression using Cox proportional hazard model with patient as random effect. Data were analyzed using R, package “coxme”.

      Results
      A total of 291 PTs (8 patients had no PT, 252 had 1 PT, 18 had 2 PTs, 1 had 3 PTs) and 627 LNs (59 patients without LN, 57 had 1 LN, 57 had 2 LNs and 106 had >=3 LNs involved) were analyzed. The majority (92%) of the patients had TNM stage III and 86% patients had ≥N2. At a median follow-up of 30 months (95%CI 27-35) and median OS of 25 months (95% CI 21-29), 47 PTs had progression and 14 LNs had progression, 38% patients had systemic relapse. The log(Vol), SUVmax and lesion type (TP vs. LN) were each significant (p<0.001) as prognostic factor for progression in the univariate cox regression. In the multivariate analysis, log(Vol) remains as a significant predictor (p<0.001) with a trend toward significance for lesion type (p=0.07) (Figure 1). Figure 1

      Conclusion
      Our regimen of 66 Gy in 24fx results in excellent local-regional control in locally advanced NSCLC patients. The PT yields a significantly higher risk of progression than LNs. A larger lesion volume and higher SUVmax were associated with an increased risk of progression.

  • +

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

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Radiation Oncology + Radiotherapy
    • Presentations: 1
    • +

      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): J.J. Sonke

      • 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.