PARAT PAlliative RAdioTherapy to Lung Cancer A Randomized Multicentre Phase III Study

1. Background 1.1 Radiotherapy in lung cancer Non-small-cell lung cancer (NSCLC) is the leading cause of cancer-related death in both men and women [1]. In stage IV disease platinum-based chemotherapy yields a median overall survival (OS) of 8-10 months [2]. When diagnosed, more than 50% of the patients have distant metastases. Forty percent have signs or symptoms originating from the thorax: dyspnoea, cough, haemoptysis, recurrent pneumonia or chest pain [3]. Palliative thoracic radiotherapy can relieve symptoms originating from intra-thoracic malignancy and improves quality of life (QoL) in approximately one third of patients [4]. It is increasingly used in daily clinical practice as an alternative to chemotherapy in patients without local symptoms with the purpose of prolonging life and avoiding local thoracic symptoms. In addition, palliative radiotherapy is used to relieve symptoms before initiating systemic treatment (chemotherapy, targeted agents, immune therapy, etc). In this latter case, it is important not to delay the systemic treatment unnecessary with long schedules of radiotherapy. An optimal radiotherapy regimen will thus palliate symptoms with minimal toxicity and consider the patient's time investment, as well as be compatible with any additional treatments given. In a recent retrospective study of 159 consecutive Danish NSCLC patients who received palliative thoracic radiotherapy (2010-11) median survival was 4.2 months. One third of the patients died within two months and 22% within 30 days [5]. This further underlines the importance of not subjecting patients to prolonged, toxic treatments in their final year of life. A recent Cochrane review [6] found that there was no consistent evidence to support that longer, more fractionated radiotherapy regimens gave better or more durable palliation than shorter regimens. Furthermore, there was no significant survival advantage associated with longer regimens with higher biological radiation doses.

The most common acute toxicity is oesophagitis. It is often not technically possible to avoid high dose exposure to the oesophagus because of the target localization in proximity to the mediastinum. Radiation-induced oesophagitis is most often a reversible condition. However, it compromises swallowing due to pain, causes weight loss and deterioration of the performance state (PS) and QoL at a vulnerable time for the patient, and it may impact the possibility of receiving further anti-neoplastic treatment. The Cochrane review found that up to 50% of patients receiving palliative thoracic radiotherapy reported severe oesophagitis. The studies differed widely in terms of physician- or patient self-assessment, timing, and the method used, and no overall judgement could be made. The review concluded that toxicity was comparable between different radiotherapy regimens. However, recording and reporting of early toxicity was lacking in the included studies. This absence of early toxicity data means that the current evidence is insufficient for clinical decision making in this patient group. 2. Study design The patients will be invited to participate in the study prior to initiation of palliative radiotherapy. After signing informed consent the patients will be randomized 1:1 between two different radiotherapy dose fractionations: 30 Gy/10 F or 20 Gy/4 F. Physicians and patients will not be blinded to the randomization.

2.1 Systemic therapy Patients can receive chemotherapy, immunotherapy and targeted therapy during radiotherapy.

2.2 Study sample size and time frame According to the Danish Lung Cancer Registry, 50% of the 4700 lung cancer patients diagnosed yearly are in advanced stage. Of these, one third is supposed to benefit from palliative thoracic radiotherapy and of these, 400 patients (~50%) are expected to be enrolled on the trial each year. Since 1184 consecutive patients are required (see chapter 7) the study is expected to enrol patients over a 3-year period. Given the declared support of all Danish radiotherapy centres, this is considered a realistic time frame.

Following study closure, 3 weeks of follow-up after radiotherapy initiation will be allowed for all patients, at which point data will be collected for primary analysis. Further analysis will be performed 1 and 3 years after the last patient is enrolled. Data will be kept in databases 15 years after the last patient is included. 3. Radiotherapy treatment planning 3.1 Target and organs at risk The gross tumour volume (GTV) is defined by the referring oncologist based on a planning CT scan, and if available, a diagnostic PET/CT scan. The oncologist will note in the CRF if the GTV fully or only partially encompass all active malignant disease in the thorax. The clinical target volume (CTV) is identical to the GTV, and thus not delineated.