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Cecile Le Pechoux



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    MS07 - Controversies with Stereotactic Radiation in Early Stage Lung Cancer (ID 70)

    • Event: WCLC 2019
    • Type: Mini Symposium
    • Track: Treatment of Early Stage/Localized Disease
    • Presentations: 1
    • Now Available
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      MS07.06 - Hot Topics in SBRT - Biopsy, Central Lesions, Radiologic Evaluation (Now Available) (ID 3479)

      14:00 - 15:30  |  Presenting Author(s): Cecile Le Pechoux

      • Abstract
      • Presentation
      • Slides

      Abstract

      Stereotactic body radiotherapy (SBRT) has taken a growing place among treatment strategies in lung cancer in the past ten years because of its reported good results and favourable risk-benefit ratio especially in high-risk patients. This treatment modality allows delivering precisely a very high dose of radiation therapy to a targetable lesion, using a small number of fractions (3 to 5 more frequently). It has become the standard of care in medically inoperable peripheral early stage non-small cell lung cancer (NSCLC) patients. It is also frequently used in metastatic patients to treat cranial as well as extra-cranial metastases. Recently small randomised studies evaluating SBRT in oligometastatic NSCLC have shown promising results. Its role is now well accepted however there are situations where SBRT is still a subject of controversy and may be regarded as a hot topic

      because of the lack of pre-treatment biopsy

      because of less favourable outcome in central lesions and higher risk of complications

      because of the difficulty of radiologic evaluation

      When a peripheral lung nodule is discovered, suspect of being lung cancer, attempt should be made to obtain a pathological diagnosis before any treatment is proposed. Percutaneous CT–guided transthoracic biopsy is the established investigation in the work-up of pulmonary nodules, but there is a risk of complications such as pneumothorax (20-40%). However in patients with poor lung function (severe COPD, emphysema..), tissue sampling can be particularly challenging especially when the nodule is beyond the reach of conventional bronchoscopy. These are typically the patients that may be considered for SBRT, possibly presenting a contra-indication to transthoracic biopsy. Criteria for definition of a nodule as lung cancer without biopsy confirmation have been proposed such as progressive growth on CT imaging or presence of a hypermetabolic lesion on PET scan, and multidisciplinary tumor board consensus on the clinical diagnosis of lung cancer; there should be at least a 85% risk of malignancy, based upon accepted criteria [Postmus; Louie, Reid].

      If stereotactic radiotherapy in peripheral early NSCLC is presently a standard of care in inoperable patients due to co-morbidities and age, its role is more controversial for centrally located tumors because of less favorable outcome and higher risk of complications. In the past years, there has been a need to better classify these patients differentiating ultra-central from central lesions. The RTOG 0813 phase I/II trial, evaluated dose escalation in 120 patients with centrally-located non-small lung cancer with a five-fraction schedule that ranged from 10 to 12 Gy per fraction [Bezjak 2019]. The maximum tolerated dose was 60 Gy (5 fractions of 12 Gy), which was associated to a 2 year local control rate of 87.9%. They reported a fatal hemoptysis rate of 4%, potentially attributable to stereotactic radiotherapy [Bejzak 2015]. Even if the authors of this prospective study reported that outcome was comparable with that of patients with peripheral early-stage tumors, the risk of severe toxicity seems to be higher than in peripheral tumors. In another prospective phase II study, the Nordic hilus trial, which included 74 patients with central tumors within 1 cm from the proximal bronchial tree (PBT), the administered dose was 8 fractions of 7 Gy [Lindberg]. The authors reported a grade 4-5 toxicity of 19% among patients with tumor close to the main bronchus (ultra-central location) versus 3% in patients with tumor close to a lobar bronchus (central location). In a retrospective study of 88 patients with ultra-central lesions defined as tumors abutting PBT or trachea, or close to esophagus, a grade 3 toxicity or higher was reported in about 20% patients [Wang]. In another smaller retrospective study, where patients received 12 fractions of 5 Gy, outcome was quite good but toxicity ≥ grade 3 was reported in 38% of patients [Tekatli]. Thereby stereotactic radiotherapy for ultra-central tumors cannot be considered a standard treatment and more studies are needed for all central tumours to find the optimal dose regimen.

      Radiological evaluation after SBRT is performed mostly with chest CT scan, and changes occurring early and/or late are very common but can be tricky for radiologists as well as clinicians [Ronden,Febbo]. If FDG PET-CT is well established as staging tool prior to treatment, it is generally not used for surveillance. It may be useful though to differentiate local recurrence from radiation-induced lung opacity. Ideally, a treatment failure suspicion should be confirmed with a biopsy.

      These hot topics regarding SBRT show the difficulty to include patients into prospective trials; efforts have been made and should be pursued.

      References

      Postmus PE, Kerr KM, Oudkerk M, et al. Early and locally advanced non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2017;28(suppl_4):iv1-iv21.

      Louie AV, Senan S, Patel P, et al. When is a biopsy-proven diagnosis necessary before stereotactic ablative radiotherapy for lung cancer?: A decision analysis. Chest 2014; 146(4):1021-1028.

      Reid M, Choi HK, Han X et al. Development of a Risk Prediction Model to Estimate the Probability of Malignancy in Pulmonary Nodules Being Considered for Biopsy. Chest 2019. [Epub ahead of print]

      Lindberg K, P.Bergström, OT Brustugun et al. The Nordic HILUS-Trial - First Report of a Phase II Trial of SBRT of Centrally Located Lung Tumors. J Thorac Oncol 2017;12(15) Abstract S340.

      Bezjak A, Paulus R, Gaspar LE, et al. Safety and efficacy of a five-fraction stereotactic body radiotherapy schedule for centrally located non-small-cell lung cancer: NRG Oncology/RTOG 0813 trial. J Clin Oncol 2019;37(15):1316-1325.

      C. Wang, B. Sidiqi, E. Yorke, et al. Toxicity and local control in “ultra-central” lung tumors treated with SBRT or high-dose hypofractionated RT. J Thorac Oncol 2018; 13(10).

      Tekatli H, Haasbeek N, Dahele M, et al. Outcomes of Hypofractionated High-Dose Radiotherapy in Poor-Risk Patients with "Ultracentral" Non-Small Cell Lung Cancer. J Thorac Oncol 2016;11(7):1081-1089.

      Ronden MI, Palma D, Slotman BJ, Senan S. Brief Report on Radiological Changes following Stereotactic Ablative Radiotherapy (SABR) for Early-Stage Lung Tumors: A Pictorial Essay. J Thorac Oncol 2018;13(6):855-862.

      Febbo JA, Gaddikeri RS, Shah PN. Stereotactic Body Radiation Therapy for Early-Stage Non-Small Cell Lung Cancer: A Primer for Radiologists. Radiographics 2018;38(5):1312-1336.

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    OA12 - Profiling the Multidisciplinary Management of Stage III NSCLC (ID 144)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Treatment of Locoregional Disease - NSCLC
    • Presentations: 1
    • Now Available
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      OA12.01 - PCI for Radically Treated Non-Small Cell Lung Cancer: A Meta-Analysis Using Updated Individual Patient Data of Randomized Trials (Now Available) (ID 2624)

      15:45 - 17:15  |  Author(s): Cecile Le Pechoux

      • Abstract
      • Presentation
      • Slides

      Background

      In localized non-small cell lung cancer (NSCLC), prophylactic cranial irradiation (PCI) reduced the incidence of brain metastases (BM) (relative risk 0.35), but without a demonstrated effect on overall survival (OS). This may be due to the small sample size in these individual randomized clinical trials (RCTs).

      Therefore, we aimed to assess the impact of PCI on long term OS for radically treated stage III NSCLC patients compared to observation using updated individual patient data (IPD) from RCTs.

      Method

      The main endpoint was OS and secondary endpoints were progression-free survival (PFS), BM-free survival (BMFS) and toxicity. All analyses were performed based on the intention-to-treat principle. The median follow-up was estimated using the inverse Kaplan-Meier method. The log-rank observed minus expected number of events and its variance were used to calculate individual and overall pooled hazard ratios (HRs) and 95% confidence intervals (95% CIs) with a fixed effects model. Heterogeneity was studied using the Cochrane test and I2. Survival curves and 5-year difference between arms were estimated using the Peto method. Interaction between prognostic factors (age, performance status, and histology) and treatment allocation were assessed using Cox proportional hazards models. Toxicities grade ≥ 3 were reported descriptively.

      Result

      Data on four of the seven eligible trials (SWOG 8300, RTOG 0214, Guangzhou 2005 and NVALT-11) were available for this IPD meta-analysis. In total, 924 patients were analyzed of which 68% was male, median age was 61 years, 94% of the patients had a performance status ≤ 1 and 37% had squamous histology. The median follow-up was 8.1 years. All trials provided sufficient IPD for the three endpoints, except for the SWOG 8300 trial (OS only). This trial explained inter-trial heterogeneity. Because of the qualitative interaction with the other trials (p=0.0062) it was separately analyzed (N=254). Compared to observation, OS was significantly lower for PCI in the SWOG 8300 trial (HR 1.38, 95% CI [1.07 to 1.79] p=0.013, 5-year absolute difference -0.9%, 95% CI [-5.9 to 4.1]). However, for the other trials (N=670) no significant OS difference was observed (HR 0.90, 95% CI [0.76 to 1.07] p=0.228, 5-year absolute difference 1.8%, 95% CI [-5.2 to 8.8]). PFS (HR 0.78, 95% CI [0.65 to 0.92] p=0.004, 5-year absolute difference 4.8%, 95% CI [-1.2 to 10.8]) and BMFS (0.38, 95% CI [0.27 to 0.53] p<0.001, 5-year absolute difference 20.7%, 95% CI [12.2 to 29.2]) were significantly higher in the PCI arm. There was no interaction between prognostic factors and treatment allocation for OS. Toxicity data for the PCI arm was available in all trials except the SWOG 8300 trial. The total number of patients with at least one grade ≥3 toxicity (for the adverse events pre-specified in the protocol) in the PCI arm was 19/456, including 11/86 in the NVALT-11 trial. Toxicity for the observation arm was only available in the NVALT-11 trial, including 4/88 patients with at least one grade ≥3 toxicity.

      Conclusion

      Although PFS and BM-free survival were improved for patients who received PCI, no significant PCI benefit for OS was observed.

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    P2.09 - Pathology (ID 174)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Pathology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.09-15 - PD-L1 Expression and Lymphocyte Infiltration in Resected Stage IIIAN2 NSCLC: Preliminary Data from a Lung ART Ancillary Study (ID 1344)

      10:15 - 18:15  |  Author(s): Cecile Le Pechoux

      • Abstract

      Background

      Patients with resectable stage IIIA N2 NSCLC, are at high risk of both systemic and loco-regional relapse following surgical resection, necessitating neo-adjuvant or adjuvant treatments. Prognostic biological markers are needed. Parameters from the immune microenvironment, including PD-L1 expression and lymphocytic infiltration, have been poorly described in this group of patients. Thus we assessed simultaneously PD-L1 expression and TIL density in a cohort of stage IIIA N2 Lung ART patients, and correlated the results with clinical and pathological features before adjuvant treatment.

      Method

      Formalin fixed paraffin-embedded tumor surgical specimens from 247 patients included in the Lung Adjuvant Radiotherapy Trial (NCT00410683) were studied. PD-L1 immunohistochemistry was performed centrally on whole slides using a validated clinical PD-L1 assay. Expression of PD-L1 in tumor cells (TC) and immune cell (IC) was scored by a trained pathologist. Morphological assessment of TIL density (percentage of tumor area) was performed on whole hematoxylin-eosin stained slides. Surgical and pathology reports were reviewed by an independent expert committee for tumor staging. Association between immune parameters and baseline clinical characteristics were assessed in exploratory analyses in order to provide insights on immune activity in resected NSCLC patients.

      Result

      PD-L1 expression in ≥1% TC, ≥50% TC, ≥1% IC, ≥10% IC was observed in 47.8%, 21.9%, 61.5%, 7.3% of patients, respectively. In univariate analysis, high PD-L1 expression in both tumor cells and immune cells for all cut points correlated strongly with a higher TIL density (p-values ≤0.001). In 41 (16.6%) patients with preoperative chemotherapy (CT), a higher TIL density was observed (mean 28.1 vs. 17.5%, p=0.0018) as compared to patients without preoperative CT, but no difference was noted for PD-L1 expression in both TC and IC,. Skip N2 metastases were associated with a higher TIL infiltration (mean 22.9% vs. 17.4% p=0.014). We found no significant correlation between PD-L1 or TIL infiltration with the number of mediastinal lymph nodes stations involved on pathological examination and with histological tumor subtypes (squamous cell carcinoma vs. adenocarcinoma).

      Conclusion

      PD-L1 expression levels in TC and IC appeared similar in stage IIIA N2 NSCLC as compared to other stages. Expression in both TC and IC strongly correlated with TIL infiltration, suggesting a prominently immune-induced expression mechanism. Preoperative chemotherapy was associated with a higher TIL infiltration but not higher PD-L1 expression. Patients with skip N2 metastases harbored a higher level of TIL density, a finding consistent with a more active immune microenvironment in this group of patients with better prognosis. These data will be subsequently updated on a larger number of patient and correlated to clinical follow-up.