General Aim The aim of this prospective, multicenter observational cohort study is to
determine the impact of baseline bio-behavioral stress (Aim I) on cancer progression and
survival in patients with newly diagnosed glioblastoma (GBM) undergoing standard
radiochemotherapy. The role of baseline physical activity (PA) and baseline partner's
distress as stress-modulating factors will be assessed in an exploratory analysis.
Secondary aims include a longitudinal assessment of self-reported psychological distress
in this homogenous patient cohort and their partners (Aim II) and -in a translational
subproject
- - to determine the role of serum copeptin as a biomarker for distress (Aim
III).
Specific Aims Specific Aim I: Prognostic role of stress at the time of diagnosis in GBM
patients In this analysis, baseline neuroendocrine stress will be correlated to
progression-free survival (PFS).
More specifically we aim at assessing.IA) Whether stress-induced disruption of diurnal cortisol rhythmicity as measured by the
salivary cortisol slope is an independent prognostic factor for (progression-free)
survival in patients with newly diagnosed GBM undergoing standard multimodal treatment.
IB) Whether increased baseline self-reported physical activity is correlated with lower
levels of stress (i.e. acts as a stress-modulating factor) and prolonged
(progression-free) survival.IC) Whether high levels of stress in the patients' partner (baseline diurnal cortisol
slope) are correlated with high levels of stress in the patient (i.e. stress-modulating
factor) and shorter (progression-free) survival.Specific Aim II: Longitudinal cohort of patient-partner dyads In the same cohort of
patients (Aim I above) we aim at describing distress over time (three-monthly) from start
of combined radiochemotherapy to disease progression in patients and
- - as a paired dyad -
in one close partner.
Specific Aim III: Copeptin biomarker subproject In a translational subproject we aim at
assessing the prognostic role of baseline serum copeptin- an easy to test serum biomarker
of stress in many clinical situations, which has never been assessed in cancer patients.
Methods Study design Since the prognostic role of stress in GBM has not been studied
before, we propose in a first step an observational, prospective multicenter cohort study
in a well-defined group of patients, all at the same stage of disease (initial diagnosis)
and all undergoing the same standard multimodal treatment (surgery followed by
radiochemotherapy according to R.Stupp et al.).
Patients All patients in good performance status (Karnofsky Performance Score (KPS) ≥
50%), aged 18 years and older, with histologically confirmed, previously untreated GBM
are eligible prior to starting initial treatment with radio-chemotherapy. In order to
participate, patients will need to have given their informed consent on the
ethics-approved consent form and will need to be willing and able (as judged by the
investigator) to comply with the protocol. Cardiovascular contraindications to the
6-minute walking test (6MWT) and/or a history of instable angina pectoris or New York
Heart Association (NYHA) grade II or greater congestive heart failure (according to the
Thoracic Society recommendations) preclude trial inclusion. Equally, patients who have
signs or symptoms (including laboratory findings) of conditions, either metabolic or
psychological, that interfere with adequate assessment of the stress axis (e.g. chronic
use of a corticosteroid, psychiatric disorder and medication) are excluded. Perioperative
dexamethasone treatment is not an exclusion criterion as short time treatment does not
clearly affect the HPA axis and synthetic corticosteroids can be discriminated in
salivary cortisol measurements. Inability to follow study procedures, e.g. due to
language problems, psychological disorders, dementia or confusion, is another reason for
study exclusion.
Patients' partners Each patient designates his or her closest partner, (not necessarily
intimate partners), either a person living in the same household or with daily contact
(husband/wife, not married partner, other family members). In order to participate, the
patient's partner must be older than 18 years, in a good performance status (KPS≥50%),
willing and able (as judged by the investigator) to comply with the protocol and must
give informed consent.
If the patient has no partner or the partner is not willing to be part of the trial,
participation in the cohort is still possible (the group of patients without partners
will be analyzed separately).
Primary Endpoint for Aim I The primary endpoint is PFS, i.e. the time between diagnosis
and disease progression (according to RANO criteria) or death of any cause.
Response evaluation in MRI will be done using the criteria by MacDonald et al. , which
are specified in the RANO criteria. In brief, the definitions for "progression" is the
following: At least 25% increase in the size of a solid mass or contrast-enhancing
lesions on MRI (or CT) or the appearance of a new lesion or clinical deterioration.
Secondary Endpoints for Aim I.Secondary endpoints include overall survival and measures of treatment tolerance:
- - Number of patients, who stopped treatment for reasons other than progressive disease.
- - Percentage of planned temozolomide doses received.
Study Flow and Assessments.Assessments Baseline (T1): predictor variables Baseline Assessment will occur at a
strictly defined time point (T1) in order to minimize time-dependent confounders on
predictor variables (particularly stress lab): Physical functioning tests and
questionnaires will be performed on days -3 before start of radiochemotherapy. Salivary
cortisol samples will be performed at days -2 and -1 before start of radiochemotherapy.
Baseline Consolidation (T2) The visit will take place 28d after T1 when patients have
started their treatment ("steady-state"), for all non-progressing patients (which will be
the vast majority at this early time-point) and includes the same assessments as T1. The
purpose of T2 assessments is to validate T1 i.e. to confirm that T1 (baseline) has been
representative for the condition patients and partners are in early during treatment and
to exclude that T1 assessments have been unrepresentative due to the impending start of
an unknown treatment. T2 assessments will be analyzed as confirmatory baseline prognostic
factors in all non-progressing patients.
Follow up visits until progression (FU1) Follow-up visits will be done every 12 weeks.
The purpose of the FU1 visits is i) to measure disease status in MRI for aim I (1°
endpoint) and ii) to longitudinally describe distress, emotional functioning and quality
of life (QoL) in patients and partners for aim
- II.
Follow up visits from progression to death (patients only) (FU2) After progression
patients will be contacted every three months for survival status (dead or alive).
Study procedures Stress Aim I (predictor variables): Baseline Stress measurements in
patients as well as partners at baseline (T1) and after 4 weeks (T2) i) Neuroendocrine
stress evaluations using standard laboratory essays (salivary diurnal cortisol slope,
cortisol awakening response (CAR), short adrenocorticotropic hormone (ACTH)-test as well
as ii) Self-reported psychological distress evaluations by questionnaires (distress
thermometer and perceived stress scale)
Aim II (descriptive variables): Distress in the longitudinal cohort will be evaluated
every three months in patients-partners dyads with self-reported measures such as DT and
PSS (ii above). Quality of life and emotional functioning will also be described as
measured by the FACT-Br and HADS-D score.Ad i.)
- - Diurnal Cortisol Slope: Salivary cortisol levels peak 30-60 minutes after awakening
and then drop to a nadir during sleep.
This diurnal rhythm is disrupted in
chronically stressed patients: leading to a flattening of the slope (beta) of the
curve that connects salivary cortisol concentrations over time (from awakening to
bedtime). Salivary cortisol will be measured on two consecutive days (patients will
receive a kit with "salivettes" containers to use at home and store in the
refrigerator until next day hospital visit). Salivary samples will be collected
after waking up in the morning, 30 minutes later (for CAR below), at 4pm and at 9pm.
Cortisol level analyses will be done by the immunoassay ECLIA (E170 Roche,
Switzerland) at the reference hospital (University Hospital Basel). Sample storage
and shipment can be performed at -20°C.
- - The cortisol awakening response (CAR) describes the increase of about 50% in saliva
cortisol levels, which occurs 20-30 minutes after waking up in the morning.
It is
thought to be linked to the hippocampus' preparation of the
hypothalamic-pituitary-adrenal axis (HPA) to face anticipated stress and it is
independent from the circadian variation in the HPA axis. CAR provides an easy
measure of the capacity of the HPA axis to react to stress. An increased CAR has
been associated with burnout, worry and chronic stress at work. For CAR saliva
samples will be collected on two consecutive days by passive drooling, immediately
after awakening (0') and 30 min (30') later [45].
- - As perioperative dexamethasone is usually given in these patients, a short or
"low-dose" ACTH test (Synacthen test) will be performed, to rule out relative
adrenal insufficiency.
The test reflects the adrenal function and is a validated and
save tool routinely used in daily practice. A baseline sampling of Cortisol is
performed before 1 ug Synacthen is applied by intravenous route. Stimulated Cortisol
serum level is measured exactly 30min after Synacthen application. The test will be
performed in the morning. Cortisol level analyses will be done by the immunoassay
ECLIA (E170 Roche, Switzerland).
Ad ii) The distress-thermometer (DT) is a 10-point scale displayed in a thermometer
format and was originally developed by Roth and colleagues (Appendix 1). Validity of DT
has been examined for outpatient cancer patients as well as relatives.
The perceived stress scale (PSS) is a universally accepted, standardized unidimensional
scale that assesses perceived stress by asking respondents to report whether their lives
seem to be unpredictable or uncontrollable, or if they feel overburdened. It assesses the
cognitively mediated emotional response to an objective event, rather than the objective
event itself.
Quality of life (QOL) will be measured with the Functional Assessment of Cancer Therapy
(FACT). The FACT comprises a series of questionnaires to measure general QOL, as well as
cancer- and condition-specific symptoms during and after cancer treatment. The
questionnaires are broadly used and validated in several languages, including German. The
following scales will be used: FACT-Br (brain), containing 37 items on physical
wellbeing, family/social wellbeing, emotional wellbeing and functional wellbeing. For
comparable evaluations in partners, an adapted version of the FACT-G (general) has been
generated.
Emotional functioning: The German version of the Hospital Anxiety and Depression Scale
(HADS-D) will be used to assess current levels of depression and anxiety. Each scale
comprises 7 items, which are answered on a 4-point scale. The scale is widely used to
evaluate emotional wellbeing in patients with chronic physical conditions and is
validated for the German language.
Physical activity Exercise behavior will be evaluated in patients as well as in partners
by self-reported physical activity in MET-hours per week, by Godin-Leisure-Time-Exercise
Questionnaire (GLTEQ). In this questionnaire -validated in glioma patients- patients and
partners are asked to complete a self-explanatory four-item query of usual leisure-time
exercise habits.
-Physical condition (in patients only) will be tested using an internationally
standardized test that does not need extensive equipment (which is important for
practicability in the multicenter setting): A 6-Minute walking test (6MWT) is a simple
method to evaluate functional capacity and has been tested in multiple settings. Patients
will be instructed to walk at their fastest pace and to cover the longest possible
distance over 6 minutes under the supervision of physical therapist. During exercise,
oxyhemoglobin saturation and heart rate will be monitored by pulse oximetry.
Aim III: Copeptin Arginine Vasopressin (AVP) is a hypothalamic stress hormone, which is
produced in the hypothalamus and released from the posterior pituitary. Together with
corticotropin-releasing hormone, it leads to secretion of ACTH and cortisol. With the
recent development of a novel sandwich immunoassay for copeptin (the C-terminal
glycoprotein of the pre-provasopressin), a stable and easy to measure surrogate of AVP
secretion has become available. (Direct AVP measurement is hampered by technical,
pre-analytical difficulties). As a stress hormone copeptin mirrors individual stress
levels even more subtly than cortisol.
