PRophylactic cerebral Irradiation or active MAgnetic resonance imaging surveillance in small-cell Lung cancer patients

Small-cell lung cancer (SCLC) is characterised by a rapid doubling time and
early dissemination, including to the brain. Patients with SCLC are typically
divided into those with limited-stage (LS) versus extensive-stage (ES) disease.
LS is defined as disease confined to one hemithorax (i.e., disease which can be
included in a "tolerable" radiation field). ES consists of the remainder cases
that could not be safely treated with radiotherapy initially.
About one-third of patients present with LS disease, although many of these
patients probably already have subclinical metastatic disease. Concurrent
thoracic chemoradiotherapy (CTRT) is the mainstay of the treatment of patients
with LS-SCLC because of the high likelihood of early dissemination, both
locally and distantly.
Initial platinum-based chemotherapy-immunotherapy with anti PD-L1 (atezolizumab
or durvalumab) has recently become the standard first-line treatment in
ES-SCLC. As brain metastases (BM) develop in more than 50% of ES patients,
prophylactic cranial irradiation (PCI) has been offered to SCLC patients who
respond to initial treatments to decrease the frequency of subsequent
intracranial relapse and improve survival.
While PCI is accepted as the standard of care in LS-SCLC and optional in
guidelines for ES-SCLC, recent concerns with regards to neurotoxicity and the
availability of brain MRI active surveillance have challenged the routine use
of PCI, particularly in ES SCLC. Furthermore, there are questions about the
role and sequencing of PCI in the era of immunotherapy, particularly in ES SCLC.
In order to evaluate active brain MRI surveillance in SCLC patients, we propose
to perform a randomized phase III trial comparing active brain MRI surveillance
alone (experimental arm) to brain MRI surveillance combined with PCI (control
arm) in patients with any stage SCLC.

The primary objective is to show that brain MRI surveillance alone is
non-inferior in terms of overall survival (OS) to brain MRI surveillance
combined with prophylactic cranial irradiation (PCI) for the treatment of small
cell lung cancer (SCLC).

Patients will be treated with Standard of Care treatment. patients with any
response and no brain metastases on baseline MRI brain will be randomized
betwee intervention arm (no PCI and surveillance with MRI every three months)
and control group (PCI followed by MRI every three months)

patients will be randomized in a 1:1 ratio between the 2 arms, and stratified
by country, stage of disease (limited versus extensive), use of immunotherapy
as part of the first-line treatment (yes/no), and ECOG Performance Status (0 or
1 versus 2).

Brain MRI will be performed every 3 months until month 12 and thereafter every
6 months until month 24, from randomization, regardless of delayed or
interrupted treatment.
Chest-abdomen-pelvis contrast CT scan or MRI shall be performed per
institutional standards at the discretion of the treating physician. However,
it is recommended to perform an assessment every 3 months until month 12 and
thereafter every 6 months until month 24.

Prophylactic cranial irradiation will be delivered at the dose of 25 Gy in 10
fractions to the whole brain. PCI should be initiated at the latest 14 days
post randomization.
Patients must have a brain MRI performed within 28 days before randomization
and at 3, 6, 9, 12, 18 and 24 months after randomization (see brain MRI
guidelines).
Clinical evaluation will be performed every 3 months up to month 12.
Extracranial imaging is recommended and will be performed per institutional
standards at the discretion of the treating physician.

Both groups will have brain MRI's and Quality of Life forms.
Control group will have prophylactic cranial irridiation.
Intervention group will only receive brain irridiation when brain metastases
develop. Not receiving brain irridiation when there are no brain metastases
present will result in longer cognitive failure free survival.