The number of long-term lung cancer (LC) survivors increases, however many patients are diagnosed with recurrent or new thoracic cancers. High-dose reirradiation (reRT) is promising but associated with high severe toxicity rates. Existing studies are small lacking high-quality data, with no clear correlation between toxicity risk and delivered radiotherapy (RT) dose.

This Danish multicentre prospective cohort study aims to provide a framework for collecting radiotherapy-related toxicity data, loco-regional control, and overall survival data for patients with thoracic cancer undergoing reirradiation; with the ultimate aim of providing safe reirradiation to more patients.

As a secondary aim, guidelines for dose accumulation and provisional constraints for the organs at risk will be used to establish a uniform treatment strategy for reirradiation.

The CURE Lung trial will provide high-impact, globally missing data. This project will ensure full utilization of and learning from the trial, adding SDM, PROMs, and modality referral to the trial. It will model the correlation between toxicity burden and doses, enabling individualized reRT with optimized dose prescription based on toxicity risk and patient preferences, and assisting in the decision-making on the prescription dose and optimal modality. This will ensure safe reRT for the increasing number of long-term LC survivors.

1. BACKGROUND:

   The number of long-term survivors is increasing for thoracic cancers, however, a significant proportion of lung cancer (LC) patients treated with curatively intended radiotherapy (RT) may experience locoregional recurrence or develop a new cancer. This highlights the need for effective local treatment options. Repeated high-dose RT (reRT) is a promising approach gaining traction in clinical practice. At Aarhus University Hospital (AUH), the fraction of LC patients offered curative reRT has increased from 4% in 2015 to 13% in 2024. The overall survival (OS) of reirradiated recurrent or new LC range from 7-14 months (from time of reirradiation) and depends on a variety of parameters, including tumour dose and PTV volume. ReRT has been linked to high rates of severe toxicity, leading to some patients not being offered curative reRT. Establishing solid evidence of the risks associated with reRT is crucial to offering these patients reRT on an equal footing with patients treated for their first cancer. Former studies on reRT of LC include a median of 40 (maximum 102) patients16, with diverse results on OS and no clear correlations between toxicity risk and cumulative (summed) RT doses.

2. AIM:

   Establish a framework for LC reRT based on data from CURE Lung to support clinical and shared decision-making (SDM). Four sub-studies obtain this:

   2.1 Establish a national infrastructure for reRT and implement decision-making tools to guide patient referrals to specialised modalities like proton therapy and MR-linac, ensuring optimal treatment modality selection to reRT for the individual patient.

   2.2 Integrate and analyse Patient Reported Outcome Measures (PROM), Quality of Life (QoL), and decision regret data in CURE Lung. Mapping of the patient's self-reported symptoms and correlation to toxicity data ensures an optimal overview of total disease burden and informs which patients are candidates for reRT.

   2.3 Establish and evaluate SDM focusing on the clinical risk assessment and the patient's wishes as tools for optimal patient involvement. SDM will improve the participants' knowledge, and accuracy of risk perceptions, and help them choose the best treatment, minimizing regret and improving QoL.

   2.4 Build models correlating patient- and physician-reported toxicity to RT doses, considering prior treatments, co-morbidity, and QoL to inform decision-making. This will provide dose limits for reRT, allowing individualised dose prescriptions based on toxicity risk, comorbidities and prior treatments.

3. HYPOTHESES:

   Primary hypothesis:

   - Cumulative radiation dose is related to radiotherapy-related toxicity for patients undergoing thoracic reirradiation

   Secondary hypothesis:

   - Curative reirradiation is feasible and safe for a selected patient cohort when delivered based on strict dose limits

4. PATIENTS:

   Recurrent or new LC, or solitary oligo lung metastases. The investigators plan for 500 patients in 3-4 years. Annually, approximately 100-150 patients are expected from the seven Danish RT centres based on a recent comprehensive national audit of RT retreatment numbers and sites.

5. TRIAL DESIGN AND DATA COLLECTION:

   This is a multicentre prospective registration protocol.

   The trial is based on a high mandatory standard being mandatory for participation with 1) 3D dose summation, 2) data on previous RT, systemic treatments, surgery, comorbidity and G3-4 thoracic toxicity collected at baseline, 3) prospective clinical follow-up with G2-5 toxicity scoring, and thoracic CT-imaging, performed every three months until two years and bi-annually until five years enabling reliable longitudinal toxicity scoring, and 4) pre-trial QA consisting of image registration, treatment planning and healthy tissue delineation.

   Toxicity and patient-reported outcomes (PROM) will be monitored during and up to 5 years after treatment using common terminology criteria for adverse events (CTCAE) and the European Organisation for Research and Treatment of Cancer (EORTC) QoL questionnaires (QLQ-C30 and LC13). Central databases will be used for clinical (Redcap) and dosimetric (dcmcollab) data collection.

6. PERSPECTIVES:

The CURE Lung trial will yield internationally high-impact results. The trial is based on state-of-the-art treatment delivery, dose accumulation, and clinical data collection, ensuring exceptional data quality for modelling studies. The trial data will be unique in patient numbers and data quality. Similar data are not available Worldwide. The current project will ensure full utilisation of and learning from the trial, adding SDM, PROMs, referral to specialised modalities, and high-level QA to the trial. It will enable modelling the correlation between toxicity burden and individual patient doses, paving the way for individualised reRT with optimised dose prescription based on toxicity risk and patient preferences, and assisting in the decision-making on the prescription dose and optimal modality. This will ensure safe reRT for the increasing number of long-term LC survivors.

Results will be published in scientific international journals (Radiother Oncol, Int J Radiat Oncol Biol Phys, J Clin Oncol, and J Thorac Oncol), and presented at international conferences and Danske Kræftforskningsdage.

The findings may apply to reRT for other cancers, benefitting all Danish patients. The project underpins the new work package for reRT under the Danish Comprehensive Cancer Center for RT (DCCC-RT), aiming to collect and standardize national reRT data.

Inclusion Criteria:

• Radiotherapy of thoracic lesion(s) (loco-regional lung cancer recurrence, new primary lung cancer, or solitary oligo metastasis) with the aim of long-term local control.
• Reirradiation type 1 or type 2, i.e. previous radiotherapy to the thorax as per ESTRO-EORTC consensus definition of reirradiation [Andratschke 2022]. For the sake of this study, multiple treatments to the lungs will be classified as type 2 reirradiation.
• Verification of malignancy based on biopsy. If no biopsy is available, the decision of reirradiation should be agreed upon in a multidisciplinary conference.
• Available digital dose plan(s) from former radiotherapy course(s) (DICOM files) - note that multiple re-treatments are allowed.
• Adequate lung function to tolerate treatment, at the discretion of the treating physician.
• Ability to complete a radiotherapy course with the aim of local control.
• ECOG Performance status 0-2.
• Estimated life expectancy ≥ 6 months
• Age ≥18 years
• Signed informed consent

Exclusion Criteria:

• Uncontrolled other malignancy.
• The primary and the reirradiation treatment may not be quasi-simultaneous (i.e. the two treatments should be planned independently)
• Pregnancy
• Radiotherapy to a minimum CTV mean dose of 45 Gy for SCLC and 50 Gy for NSCLC and oligometastatic lesions. Treatment schedule according to local protocols and treating physician preference.

Recurrent or new LC, or solitary oligo lung metastases. We plan for 500 patients in 3-4 years. Annually, approximately 100-150 patients are expected from the seven Danish RT centres based on a recent comprehensive national audit of RT retreatment numbers and sites.