Cognitive sequelae of Prophylactic Cranial Irradiation in non-small cell lung cancer patients

Brain metastases are one of the major signs of failure in the treatment of
patients with stage III non-small cell lung cancer (NSCLC). Prophylactic
cranial irradiation (PCI) has been shown to reduce the incidence of brain
metastases in patients with NSCLC to the same extent as in limited disease
small-cell lung cancer. However, the exact value of PCI in stage III NSCLC
patients, treated with contemporary chemo-radiation schedules with or without
surgery, is unsettled.
A randomized phase III study is currently conducted to investigate whether PCI
should become the standard of care in patients with stage III NSCLC who are
treated with curative intention. The hypothesis of this study is that PCI will
prevent brain metastases, even for patients with other sites of failure, and
that PCI will improve the neurological disease-free survival, and hence
health-related quality of life (HRQOL).

From clinical observations can be learned that a subgroup of patients
experiences adverse sequels. Observed symptoms include predominantly mental
slowing and fatigue, interfering with daily life activities. The recent study
of Slotman et al. (JCO 2009) confirms the occurrence of such adverse effects on
cognitive functioning and other HRQOL parameters of PCI. Unfortunately, only
short-term data were available in this study and conclusions could be drawn
from patients* self-reported data only. To address cognitive functioning
properly, objective testing by means of standardized neuropsychological tests
is the method of choice in assessing neuropsychological problems, as
self-reported cognitive complaints are clearly linked to and tend to reflect
also other processes, such as depressive, anxiety or fatigue symptoms.

The goal of PCI is to increase the neurological disease-free survival, without
significant side effects, and hence to improve HRQOL.

This sub-study aims to investigate this expected advantage of PCI in NSCLC in
maintaining function and increasing HRQOL by using all adequate measures to
detect significant side effects, i.e. objective assessment of cognitive
symptoms alongside self-reported symptoms and assessment of ADL function, in a
large enough sample size with long-term follow-up data.

This neuropsychological sub-study is a longitudinal observational study in
which NSCLC patients randomized to receive PCI or not will be followed over
time.

Patients will be tested 5 times maximally:
1. At baseline (i.e. after radical treatment and after registration but before
randomization to PCI or not)
2. 3 months after randomization of PCI
3. 6 months after randomization of PCI
4. 12 months after randomization of PCI
5. 24 months after randomization of PCI
Patients in the observation arm will be assessed at similar time interval.

The additional MRI scan performed for the purpose of the neuropsychological
study will take place in the weeks preceeding the 12 months assessment point
randomization.

The neuropsychological assessment points coincide with the evaluations points
in the main trial protocol.

Patients will be examined maximally 5 times over a period of 24 months. Each
test assessment will last 15 minutes and consists of several neuropsychological
tests. The additional neuropsychological examination does no pose any risk for
patients. Ample experience with many patient populations has indicated that
such a procedure is feasible and is not considered too burdensome. The addition
MRI scan performed for the purpose of this study in the weeks before
neuropsychological assessment at 12 months may elucidate the existence of a
metastasis, that otherwise would potentially remain unnoticed for a given
period of time. This early detection of brain metastasis could negatively
impact the well-being of the patients and his/her significant others; on the
other hand timely treatment could be offered at this stage.
Knowledge on the effects of PCI on cognitive functioning may aid to early
detection of cognitive impairment and appropriate guidance of patients (and
their relatives) confronted with such impairment and is essential in the
discussion on the benefit of PCI.