Improved Radiotherapy and medical treatment
Ansvarlig/responsible:
Tine Schytte, overlæge, onkologisk afdeling, Odense Universitetshospital
Projekt 2: Identifying parameters influencing loco-regional control and overall survival
Link til dansk resume
Link to english summary
Projekt 1: Forekomsten af hjertesygdom som følge af strålebehandling hos patienter med lunge- og spiserørskræft i Danmark
Status oktober 2023
Background
The treatment of choice for inoperable lung cancer is radiotherapy (RT). Local control rates are above 90% for stage I peripherally located NSCLC treated with stereotactic high dose RT. Locally advanced lung cancer are difficult to treat to the same high doses without high risk of severe radiation induced toxicity. For these patients, progression free survival and overall survival at 5 years are 18% and 32%. In patterns of failure analysis local, regional and distant failure rates are 38, 36 and 52%.To improve these discouraging results the randomized phase III trial NARLAL2 (NCT02354274) for locally advanced NSCLC (IIB-IIIB) is initiated by the DLCG subgroup, DOLG (the Danish Oncologic Lung Cancer Group). In NARLAL2 the RT dose is heterogeneously increased within the tumor prioritizing the most FDG-PET avid tumor areas. While RT dose escalation aims at improving local control, the high distant failure rate calls for improvement of the systemic treatment. In the resent PACIFIC trial 1-year of durvalumab after concomitant chemoradiation improves overall survival substantially with a HR of 0.68. To accommodate the promising results of the PACIFIC trial, NARLAL2 will be amended to include adjuvant durvalumab. Translational research collects repeated PET-CT scans and blood samples during and after treatment to allow for detailed response analyses.
The work in CP6 was divided in three subprojects
Subproject1: Heart disease caused by Radiotherapy
As overall survival increases, it is essential to minimize radiation induced side effects. Side effects caused by irradiation of the heart during RT of lung cancer is not well described, but data from lymphoma and breast cancer show increased heart disease and heart related mortality after radiotherapy. In this subproject, a PhD project investigates heart disease for lung cancer patients and aims at identifying pre-treatment risk factors that can predict patient with high risk of heart disease – specifically the impact of calcium in the coronary arteries is investigated since a high calcium score is known to predict heart disease in a general patient population. This knowledge will enable monitoring, early detection, and treatment of heart disease for high-risk patients thereby improving their outcome.
Analysis relied on data from 801 Danish patients with locally treated at OUH (138), AUH (154), Vejle (126), RH (141), Herlev (150), and Aalborg (100).
Results:
The first analysis evaluated if coronary artery calcium score (CACS) had an impact on overall survival in patients with locally advanced non-small cell lung cancer treated with definitive radiotherapy. CACS did not add prognostic information to the population’s classical risk factors, such as tumor volume, performance status, and age.
Secondly the association between OS and irradiation of lung and heart was evaluated. We found that, lung and heart doses had a negative impact on survival. Furthermore, the data indicated that the left side of the heart is especially radiation dose-sensitive. The data indicate that overall heart irradiation should be reduced to improve the OS if possible.
As a spin-off project, an open-source auto-segmentation algorithm for delineating heart and substructures were developed and validated.
Budget: 300.000 DKK
The salary for the PhD study has been funded from University of Southern Denmark (1 man-year), DCCC (200.000 DKK), “Knæk Cancer” (430.000 DKK), Department of Oncology, OUH (150.000 DKK).
Publications:
Olloni A, Brink C, Lorenzen EL, Jeppesen SS, Hofmann L, Kristiansen C, Knap MM, Møller DS, Nygård L, Persson GF, Thing RS, Sand HMB, Diederichsen A, Schytte T. Heart and Lung Dose as Predictors of Overall Survival in Patients With Locally Advanced Lung Cancer. A National Multicenter Study. JTO Clin Res Rep. 2024 Mar 14;5(4):100663. doi: 10.1016/j.jtocrr.2024.100663. PMID: 38590728; PMCID: PMC10999485.
Olloni A, Lorenzen EL, Jeppesen SS, Diederichsen A, Finnegan R, Hoffmann L, Kristiansen C, Knap M, Milo MLH, Møller DS, Pøhl M, Persson G, Sand HMB, Sarup N, Thing RS, Brink C, Schytte T. An open source auto-segmentation algorithm for delineating heart and substructures – Development and validation within a multicenter lung cancer cohort. Radiother Oncol. 2024 Feb;191:110065. doi: 10.1016/j.radonc.2023.110065. Epub 2023 Dec 19. PMID: 38122851.
Olloni A, Brink C, Lorenzen EL, Jeppesen SS, Hoffmann L, Kristiansen C, Knap MM, Møller DS, Nygård L, Persson GF, Thing RS, Sand HM, Diederichsen A, Schytte T. Does coronary artery calcium score have an impact on overall survival for locally advanced non-small cell lung cancer treated with definitive radiotherapy. Radiother Oncol. 2023 Aug;185:109719. doi: 10.1016/j.radonc.2023.109719. Epub 2023 May 29. PMID: 37257588.
Subproject 2: Identifying parameters influencing loco-regional control and overall survival
Relating pre-treatment parameters to the risk of failure in terms of either loco-regional or distant recurrence after radiotherapy will enable patient-specific risk adapted treatment strategies, where i.e. patients prone to fail loco-regionally will receive intensified radiotherapy treatment. Based on data from Rigshospitalet a competing risk model for first site of failure after definitive chemoradiotherapy for inoperable NSCLC was published [J Thorac Oncol. 2018 13:559-567]. The model uses pre-treatment performance status (PS), stage, histology, concomitant chemotherapy, gender, age, tumor size, SUVpeak of the primary tumor and the lymph nodes with the highest uptake to predict the type of failure or death. In this study, we test the published model in an independent external validation cohort form Aarhus University Hospital. In the NARLAL2 trial different Radiotherapy dose levels are applied and the data from NARLAL2 can potentially be used to extend the model to also consider the RT dose received by the tumor.
Results:
An analysis of early mortality after curative intent chemoradiation of locally advanced NSCLC revealed that the 180-days mortality rate was 10%. There was no discernible high-risk period. Age, sex, histology, and performance status significantly impacted the risk. The Charlson Comorbidity Index and TNM stage did not significantly impact the risk.
The external validation of the competing risk model for first site of failure after definitive chemoradiotherapy for inoperable NSCLC based on pre-treatment variable are finalized and the scientific manuscript is under preparation. The data support the original model.
Budget: 200.000 DKK,
The project has also received funding (120.000 DKK) from DCCC.
Publications:
Jensen KH, Persson G, Pøhl M, Frank MS, Hansen O, Schytte T, Kristiansen C, Knap M, Skovborg M, Vogelius IR, Friborg J. Early Mortality After Curative-intent Radiotherapy in Patients With Locally Advanced Non-small Cell Lung Cancer-A Population-based Cohort Study. Clin Oncol (R Coll Radiol). 2024 Sep 4:S0936-6555(24)00377-7. doi: 10.1016/j.clon.2024.08.015. Epub ahead of print. PMID: 39306558.
Lutz, C. M., Knap, M. M., Møller, D. S., Hoffmann, L., Khalil, A. A., Håkansson, K. E., … & Vogelius, I. (2021). PD-0876 First-failure prediction model for locally advanced non-small cell lung cancer-External validation. Radiotherapy and Oncology, 161, S712-S713. Abstract
Subproject 3: Analysis of the primary endpoint in the NARLAL2 trial
The NARLAL2 trial has included 301 of 352 patients and is expected to include the last patient by the beginning of 2023. Patients from Aarhus, Vejle, Odense, Herlev, and RH are included in the trial. The primary endpoint (loco-regional tumor control) and outcome in terms of overall survival and early toxicity will be published in two papers. Dose escalation in the NARLAL2 trial comes with the risk of toxicity and the early results of safety in terms of toxicity will be published 3 months after the last patient is randomized. The results on the impact on loco-regional control as well as overall survival will be published 9 months after the last patient is randomized.
Results:
All 352 patients have been included and 1-year follow-up is reached.
A preliminary primary endpoint analysis was presented at ESTRO 2024, and overall survival data was presented at ASCO 2024. The final analysis is under evaluation and will be submitted for publication late 2024.
The early toxicity analysis is submitted for review and publication. The data shows that patients in the dose escalated arm did NOT experience excess toxicity compared to patients who received standard radiotherapy.
Budget: 500.000 DKK
The budget post 01.09.22-31.08.23 were used to prepare data for analysis and analyze the early toxicity, while the budget post 01.09.23-31.08.24 were used to analyze the primary endpoint.
Publications:
Schytte T. et al., Overall survival following heterogeneous FDG-guided dose-escalation for locally advanced NSCLC in the international phase III NARLAL2 trial.JCO 42, LBA8069-LBA8069(2024). DOI:10.1200/JCO.2024.42.17 suppl.LBA8069. Scientific Abstract
Lutz, C. M., Nielsen, T. B., Lund, M. D., Schytte, T., Hansen, T. S., Hoffmann, L., … & Møller, D. S. (2024). 2381: Inhomogeneous dose escalation for NSCLC: Full dosimetric analysis of the phase III NARLAL2 trial. Radiotherapy and Oncology, 194, S1736-S1739. Scientific Abstract
Schytte, T., Kristiansen, C., Appelt, A., Khalil, A., Brink, C., Lutz, C. M., … & Knap, M. (2024). 3531: The NARLAL II trial: First results on loco-regional control in stage 3 NSCLC. Radiotherapy and Oncology, 194, S117-S119. Scientific Abstract
Publikationer
Does Coronary artery calcium score have an impact on overall survival for locally advanced non-small cell lung cancer treated with definitive radiotherapy. A Olloni, C Brink, EL Lorenzen, SS Jeppesen, L Hofmann, C Kristiansen, MM Knap(, DS Møller, L Nygård, GF Persson, RS Thing, HM Sand, A Diederichsen, T Schytte. DOI: 10.1016/j.radonc.2023.109719
An open source auto-segmentation algorithm for delineating heart and substructures – Development and validation within a multicenter lung cancer cohort. A Olloni, EL Lorenzen, S Jeppesen, A Diederichsen, R Finnegan, L Hoffmann, C Kristiansen, MM Knap, MLH Milo, D Møller, L Nygård, G Persson, HMB Sand, N Sarup, R Thing, C Brink, T Schytte. DOI:10.1016/j.radonc.2023.110065
Heart and Lung Dose as Predictors of Overall Survival in Patients with Locally Advanced Lung Cancer. A National Multicenter study. Olloni A, Brink C, Lorenzen EL, Jeppesen SS, Hoffmann L, Kristiansen C, Knap MM, Møller DS, Nygård L, Persson GF, Thing, RS, Sand HMS, Diederichsen A, Schytte T. Submitted to Journal og Thoracic Oncology