Neoplasms Clinical Trial
Official title:
Stress, Exercise Behavior and Survival in Patients With Newly Diagnosed Glioblastoma and in a Close Partner (TOGETHER-study): a Prospective Multicenter Cohort Study.
Glioblastoma multiforme (GBM) is the most common malignant central nervous system (CNS)
tumor in adulthood with a median survival of 12-16 months. The drastically shorted life
expectancy, intellectual changes and rapid physical decline in those patients are
devastating and do impose a profound chronic stress on patients and their families. There is
extensive evidence that chronic stress can promote cancer growth and progression. In the
setting of GBM patients, three major questions still have to be answered and will be
analysed in this study:
1. Is there a prognostic significance of stress in patients with newly diagnosed GBM on
treatment tolerance and (progression free) survival?
2. Can this stress be modulated by other factors, like stress of patients partners and
patients physical activity, a known independent prognostic factor in recurrent glioma
patients?
3. How is the longitudinal course of patients and partners stress and physical condition
over the disease course and do they influence (progression free) survival?
Answers to these questions will help to establish future projects studying non drug
interventions in patients and patients partners to help improving clinical and tumor related
outcome in patients with newly diagnosed GBM.
The investigators hypothesize that chronic stress, specifically measured as a disruption of
the diurnal cortisol rhythmicity, is an independent prognostic factor in patients with GBM.
Furthermore, physical activity of patients and stress level in patients` partners may impact
- as stress-modulating factors- on stress in patients and on their prognosis.
Aiming at identifying stress-related prognostic factors as potential targets for novel
treatment approaches, we propose, in a first step, a prospective multicenter cohort study:
all patients with newly diagnosed GBM and good performance status (KPS ≥ 50%) who undergo
standard treatment with combined radiochemotherapy with temozolomide (RCT) followed by 6
month of cyclic temozolomide, are eligible. In addition, one "partner", defined as a close
person living in the same home or close daily contact to the patient, will be asked for
inclusion.
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.
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