HERAN-Heterogeneously Hypofractionated Radiotherapy for Locally Advanced NSCLC

1.1 Radiotherapy in lung cancer The options for patients with locally advanced non-small cell lung cancer (NSCLC) who are not candidates for a standard definitive chemoradiotherapy regime are meagre. These patients are not fit for a standard chemoradiotherapy due to either tumour extent, resulting in excessive dose to the healthy tissue in the thorax, or with performance status not supporting seven weeks of intensive treatment. Such patients could benefit from a treatment offering long-term locoregional control leading to improved survival. However, at present, they are offered palliative treatment regimens. Alternatively, a full schedule of definitive chemoradiotherapy is sometimes attempted, and patient may only complete part of the treatment course.

Favourable alternative treatment options for this group of patients would have to:

• Provide a reasonable probability of locoregional disease control.
• Result in less expected toxicity.
• Be delivered using a shorter treatment schedule than the current 6-7 weeks Standard chemoradiotherapy aims at delivering a homogeneous dose distribution to the primary tumour and involved lymph nodes. However, studies of patterns of failures in locally advanced NSCLC patients indicate that isolated mediastinal nodal failures are less common than disease recurrence in the primary tumour site or in bulky lymph nodes. This suggests that it might be possible to lower the dose to all or selected parts of the involved mediastinal lymph nodes without drastically impacting the combined locoregional control.

Modelling studies indicate that tumour control may mainly depend on mean tumour dose, provided that the minimum dose to the tumour exceeds a certain level. One example is provided by stereotactic radiotherapy (SBRT), where very heterogeneous dose distributions usually results in higher dose in the middle of the tumour compared to the dose to the tumour periphery. The Danish NARLAL2 trial [NCT02354274] investigates heterogeneous dose escalation; with the most PET-avid part of the tumour used as a driver for the dose escalation. Most prospective trials have focused on hyperfractionated, accelerated treatments. Although effective, these schedules are also associated with substantial acute toxicity, likely not tolerable for borderline curative patients with extensive local disease. Definitive moderately hypofractioned radiotherapy has limited clinical evidence in lung cancer patients, but has demonstrated promising outcomes in a few trials. The current study aims to use a heterogeneous hypofractionated schedule for the treatment of high-risk locally advanced NSCLC patients, in order to improve loco-regional control and survival. The central idea is to decrease dose to normal tissue by ascribing a heterogeneous dose to the PTV. The gross volume of the primary tumour and bulky lymph nodes receive mean doses of up to 66 Gy in 24 fractions, and thus receive a hypofractionated higher biological effective dose than standard 66 Gy in 33 fractions.

1.2 Aim of this study To study the efficiency as well as the safety of a new treatment option of heterogeneously hypofractionated radiotherapy for patients with locally advanced NSCLC who are not candidates for standard, high-dose chemoradiotherapy, either due to excessive irradiation of normal tissue (defined as category A patients) or due to fragility of the patient (category B patients).