• ESTRO ACROP guidelines for target volume definition in the thoracic radiation treatment of small cell lung cancer

      Le Pechoux, C.; Faivre-Finn, Corinne; Ramella, S.; McDonald, F.; Manapov, F.; Martin Putora, P.; Slotman, B.; De Ruysscher, D; Ricardi, U.; Geets, X.; et al. (2020)
      Radiotherapy (RT) plays a major role in the treatment of small cell lung cancer (SCLC). Therefore, the ACROP committee was asked by ESTRO to provide recommendations on target volume delineation for standard clinical scenarios in definitive (chemo)-radiotherapy (CRT), adjuvant RT for stages I-III SCLC and consolidation thoracic RT for stage IV disease. The aim of these guidelines is to standardise and optimise the process of RT treatment planning for clinical practice and prospective studies. The process for the development of the guidelines included the evaluation of a structured questionnaire followed by a consensus discussion, voting and writing process within the committee. Firstly, we provide recommendations for both the imaging to be performed as part of the diagnostic work-up and for the RT planning process. Secondly, recommendations are made for target volume delineation including delineation of the primary gross tumour volume (GTV) and lymph node GTV and clinical tumour volume (CTV) expansion in the context of definitive and adjuvant RT. With regard to internal target volume (ITV) and planning target volume (PTV) definitions, we make recommendations about the management of geometric uncertainties and target motion. Finally, we provide our opinions on organ at risk (OAR) delineation and organisational issues to be considered. Keywords: Conformal Radiotherapy; Small Cell Lung Cancer; Target volumes; combined modality treatment.
    • An international randomized trial, comparing post-operative conformal radiotherapy (PORT) to no PORT, in patients with completely resected non-small cell lung cancer (NSCLC) and mediastinal N2 involvement: Characterisation of PORT efficacy in lung ART (IFCT-0503, UK NCRI, SAKK)

      Le Pechoux, C.; Barlesi, F.; Pourel, N.; Faivre-Finn, Corinne; Lerouge, D.; Zalcman, G.; Antoni, D.; Lamezec, B.; Nestle, U.; Boisselier, P.; et al. (2021)
      Background Primary analysis of Lung ART trial has shown (ESMO 2020) a non-statistically significant effect of PORT on disease-free survival (DFS) in N2 NSCLC patients (HR = 0�86 (95% CI 0�68-1�08]; p=0�18). However PORT was associated with a reduction of 51% in the risk of mediastinal relapse (MR). Patterns of relapse as well as prognostic factors of PORT efficacy warranted further investigations to determine which patients could benefit more from PORT. Methods Patients were eligible in Lung ART if they had a WHO performance status ?2, considered to have undergone complete resection with lymph node exploration, proven N2 disease +/- prior neo-adjuvant or adjuvant CT. DFS components (metastatic, mediastinal relapses and deaths) were analysed using competing risks approaches. Prognosis factors for DFS and OS were explored based on prespecified analyses coupled with an exploratory approach. Results 501 patients were randomised. Among DFS events, there are 161 (54%) metastatic relapses (including 61 (21%) brain metastases), 106 (36%) MR, and 29 (10%) deaths. Three-year metastatic relapse-free survival is 72.31% [66.5;77.1] and 68.47% [61.7;74] in the control and PORT arms, respectively; 3-year MR-free survival is 72.26% [65.9;77.4] and 86.06% [81.2;89.7], respectively. MR occurs mainly within initially involved nodes (66% in control arm, 47% in PORT arm) and significantly less in PORT arm (unadjusted sub-distribution HR= 0.46 (95% CI [0.3;0.7]). The 3 most frequent sites of MR are stations 7 (47%), 4L (42%), 4R (37%) for left-sided tumours; stations 4R (48%), 2R (44%) and 7 (41%) for right-sided tumours. Prognostic factors for DFS include quality of resection, extent of mediastinal involvement and lymph node ratio (involved / explored), with differential effects according to DFS components. With regards to overall survival, extent of nodal involvement is a significant prognostic factor whereas PORT (HR = 0.98 [0.7;1.4]) is not. Conclusions Use of PORT in N2 NSCLC patients reduces the risk of MR, but has no significant impact on DFS. Prognostic factors associated with different DFS components were identified which may allow a personalized prescription of PORT.
    • An international randomized trial, comparing post-operative conformal radiotherapy (PORT) to no PORT, in patients with completely resected non-small cell lung cancer (NSCLC) and mediastinal N2 involvement: Primary end-point analysis of LungART (IFCT-0503, UK NCRI, SAKK) NCT00410683

      Le Pechoux, C.; Pourel, N.; Barlesi, F.; Faivre-Finn, Corinne; Lerouge, D.; Zalcman, G.; Antoni, D.; Lamezec, B.; Nestle, U.; Boisselier, P.; et al. (2020)
      Background: Adjuvant PORT has been controversial since publication of a metaanalysis showing PORT could be deleterious especially in pN0 pN1 pts. However, changes have taken place in the management of stage IIIAN2 NSCLC pts including use of adjuvant chemotherapy (CT), patients’ workup, quality of surgery and radiotherapy. Therefore the role of PORT warranted further investigations in high risk pts. Methods: LungART is a multi-institutional randomized phase III trial comparing mediastinal PORT (54 Gy/27-30 fractions) to no PORT. Ptswere eligible if theywere PS 0-2, had a complete resection with nodal exploration, proven N2 disease; prior (neo)-adjuvant CT was allowed. The main end-point was disease-free survival (DFS). 500 pts and 292 events were required to showan improvement in DFS from30%to 42%withPORT (bilateral test). Secondary endpoints included toxicity, local control, patterns of recurrence, overall survival (OS), second cancers, prognostic and predictive factors of treatment effect. Results: Between August 2007 and July 2018, 501 patients were randomized after surgery or after CT: 252 pts allocated to PORT, and 249 to CA. Median age was 61 (range¼36-85), 66% male, histology: mostly adenocarcinoma (73%) and work-up included PET scan in 91% pts. Most patients received CT (post op 77%, pre-op 18%). Analysis for DFS was performed with a median FU of 4.8 yrs; toxicity evaluated on 487 pts (246 in CA). Early and late Gr 3-5 cardio-pulmonary toxicity was respectively 7 and 20% in PORT vs 3,2 and 7,7 % in CA. DFS hazard ratio was 0.85 (95% CI 0.67; 1.07); p¼0.16; median DFS was 30.5 months in PORT arm [24;48] and 22.8 in CA [17;37]; 3- year DFS was 47.1% with PORT vs 43.8% with no PORT. 3-year OS was 66.5% with PORT vs 68.5% with no PORT. Conclusions: LungART is the first European randomized study evaluating modern PORT after complete resection, in pts selected predominantly with PET scan and having received (neo)adjuvant CT. 3-year DFS was higher than expected in both arms and PORT was associated with a non-statistically significant 15% increase in DFS among stage IIIAN2 pts.
    • Once daily versus twice-daily radiotherapy in the management of limited disease small cell lung cancer - Decision criteria in routine practice

      Glatzer, M.; Faivre-Finn, Corinne; De Ruysscher, D; Widder, J.; Van Houtte, P.; Troost, E. G. C.; Dahele, M. R.; Slotman, B. J.; Ramella, S.; Pottgen, C.; et al. (2020)
      BACKGROUND: In limited disease small cell lung cancer (LD-SCLC), the CONVERT trial has not demonstrated superiority of once-daily (QD) radiotherapy (66 Gy) over twice-daily (BID) radiotherapy (45 Gy). We explored the factors influencing the selection between QD and BID regimens. METHODS: Thirteen experienced European thoracic radiation oncologists as selected by the European Society for Therapeutic Radiation Oncology (ESTRO) were asked to describe their strategies in the management of LD-SCLC. Treatment strategies were subsequently converted into decision trees and analysed for agreement and discrepancies. RESULTS: Logistic reasons, patients performance status and radiotherapy dose constraints were the three major decision criteria used by most experts in decision making. The use of QD and BID regimens was balanced among European experts, but there was a trend towards the BID regimen for fit patients able to travel twice a day to the radiotherapy site. CONCLUSION: BID and QD radiotherapy are both accepted regimens among experts and the decision is influenced by pragmatic factors such as availability of transportation.
    • Role of postoperative radiotherapy in the management for resected NSCLC - decision criteria in clinical routine pre- and post-lungART

      Süveg, K.; Le Pechoux, C.; Faivre-Finn, Corinne; Putora, P. M.; De Ruysscher, D; Widder, J.; Van Houtte, P.; Troost, E. G. C.; Slotman, B. J.; Ramella, S.; et al. (2021)
      Background: The role of postoperative radiation therapy (PORT) in stage III N2 NSCLC is controversial. We analyzed decision-making for PORT among European radiation oncology experts in lung cancer. Methods: Twenty-two experts were asked before and after presentation of the results of the LungART trial to describe their decision criteria for PORT in the management of pN+ NSCLC patients. Treatment strategies were subsequently converted into decision trees and analyzed. Results: Following decision criteria were identified: extracapsular nodal extension, incomplete lymph node resection, multistation lymph nodes, high nodal tumor load, poor response to induction chemotherapy, ineligibility to receive adjuvant chemotherapy, performance status, resection margin, lung function and cardiopulmonary comorbidities. The LungART results had impact on decision-making and reduced the number of recommendations for PORT. The only clear indication for PORT was a R1/2 resection. Six experts out of ten who initially recommended PORT for all R0 resected pN2 patients no longer used PORT routinely for these patients, while four still recommended PORT for all patients with pN2. Fourteen experts used PORT only for patients with risk factors, compared to eleven before the presentation of the LungART trial. Four experts stated that PORT was never recommended in R0 resected pN2 patients regardless of risk factors. Conclusion: After presentation of the LungART trial results at ESMO 2020, 82% of our experts still used PORT for stage III pN2 NSCLC patients with risk factors. The recommendation for PORT decreased, especially for patients without risk factors. Cardiopulmonary comorbidities became more relevant in the decision-making for PORT.
    • Role of radiotherapy in the management of brain metastases of NSCLC - Decision criteria in clinical routine

      Glatzer, M.; Faivre-Finn, Corinne; De Ruysscher, D; Widder, J.; Van Houtte, P.; Troost, E. G. C.; Slotman, B. J.; Ramella, S.; Pöttgen, C.; Peeters, S. T. H.; et al. (2020)
      Background: Whole brain radiotherapy (WBRT) is a common treatment option for brain metastases secondary to non-small cell lung cancer (NSCLC). Data from the QUARTZ trial suggest that WBRT can be omitted in selected patients and treated with optimal supportive care alone. Nevertheless, WBRT is still widely used to treat brain metastases secondary to NSCLC. We analysed decision criteria influencing the selection for WBRT among European radiation oncology experts. Methods: 22 European radiation oncologist experts in lung cancer as selected by the European Society for Therapeutic Radiation Oncology (ESTRO) for previous projects and by the Advisory Committee on Radiation Oncology Practice (ACROP) were asked to describe their strategies in the management of brain metastases of NSCLC. Treatment strategies were subsequently converted into decision trees and analysed for agreement and discrepancies. Results: 9 decision criteria (suitability for SRS, performance status, symptoms, eligibility for targeted therapy, extra-cranial tumour control, age, prognostic scores and "Zugzwang" (the compulsion to treat)) were identified. WBRT was recommended by a majority of the European experts for symptomatic patients not suitable for radiosurgery or fractionated stereotactic radiotherapy. There was also a tendency to use WBRT in the ALK/EGFR/ROS1 negative NSCLC setting. Conclusion: Despite the results of the QUARTZ trial WBRT is still widely used among European radiation oncologist experts.
    • Treatment of brain metastases in small cell lung cancer: Decision-making amongst a multidisciplinary panel of European experts

      Putora, P. M.; Fischer, G. F.; Fruh, M.; Califano, Raffaele; Faivre-Finn, Corinne; Van Houtte, P.; McDonald, F.; Nestle, U.; Dziadziuszko, R.; Le Pechoux, C.; et al. (2020)
      Background: Brain metastases (BM) are common in patients with small cell lung cancer (SCLC). In recent years, the role of whole brain radiotherapy (WBRT) for brain metastases in lung cancer is being reevaluated, especially in the context of new systemic treatments available for SCLC. With this analysis, we investigate decision-making in SCLC patients with BM among European experts in medical oncology and radiation oncology. Methods: We analyzed decision-making from 13 medical oncologists (selected by IASLC) and 13 radiation oncologists (selected by ESTRO) specialized in SCLC. Management strategies of individual experts were converted into decision trees and analyzed for consensus. Results and conclusion: In asymptomatic patients, chemotherapy alone is the most commonly recommended first line treatment. In asymptomatic patients with limited volume of brain metastases, a higher preference for chemotherapy without WBRT among medical oncologists compared to radiation oncologists was observed. For symptomatic patients, WBRT followed by chemotherapy was recommended most commonly. For limited extent of BM in symptomatic patients, some experts chose stereotactic radiotherapy as an alternative to WBRT. Significant variation in clinical decision-making was observed among European SCLC experts for the first line treatment of patients with SCLC and BM.
    • Validation of the impact of heart base dose on survival in NSCLC patients from the PET-Plan Trial

      Craddock, M.; Nestle, U.; Schimek-Jasch, T.; Kremp, S.; Lenz, S.; Price, G.; Salem, A.; Faivre-Finn, C.; van Herk, M.; McWilliam, A.; et al. (2021)
      Purpose or Objective Heart dose has emerged as an independent predictor of overall survival in non-small cell lung cancer patients. Several studies have identified the base of the heart as the most significant region and a potential target for cardiac sparing. This work aims to further validate the impact of heart base dose in the multicentre, randomised PET-plan trial data and for the first time, will determine whether the effect remains significant when baseline cardiac function is included in the analysis. Material and Methods 205 patients with inoperable UICC stage II/III non-small cell lung cancer treated with 60-72 Gy in 2 Gy fractions in the PET Plan randomised controlled trial (NCT00697333) were included in this study.  CT scans and dose distributions were spatially normalised to a reference patient using the “NiftyReg” deformable image registration package.  For a given time point, mean dose distributions were calculated for the alive and dead patients, censored for follow-up. Dose differences between the groups were calculated and tested for significance by comparison to the null hypothesis dose difference distribution approximated by permutation testing. An anatomical region of interest was defined at 95% of the maximum t-value in the dataset and the mean dose to the region was extracted for all patients. A uni-variable analysis tested the association of survival with dose to the identified region, clinical variables including age, gender, performance status, tumour volume and baseline ejection fraction measured prior to radiotherapy.  All variables were then included in a multivariable Cox proportional hazards model. Results 172 patients remained after processing and censoring for follow-up.  At 2-years post treatment, a highly significant region was identified within the base of the heart (p < 0.005), centred on the origin of the left coronary artery and the region of the atrioventricular node (Figure 1). The median dose to the region was 33.5 Gy. Uni-variable analyses determined worse performance status, ejection fraction less than 50%, tumour volume and mean dose to the defined cardiac region to be significant. In multi-variable analysis, performance status (p = 0.03, HR: 5.69, 95% CI: 1.21 – 26.71), ejection fraction (p = 0.008, HR: 2.91, 95% CI: 1.32-6.40) and mean dose to the cardiac sub-region (p = 0.01, HR: 1.02, 95% CI: 1.00-1.03), remained significant (Table 1). Conclusion This work validates previous image-based data mining studies in identifying a cardiac region within the base of the heart as strongly associated with overall survival.  Importantly, for the first-time baseline cardiac function was included with mean dose to the identified region in the multi-variable analysis. Poor ejection fraction did not negate the impact of dose to the base of the heart on survival.