cancers

Study Protocol
Multimodal Web-Based Intervention for Cancer-Related
Cognitive Impairment in Breast Cancer Patients: Cog-Stim
Feasibility Study Protocol
Giulia Binarelli 1,2, * , Marie Lange 1,2,3 , Mélanie Dos Santos 1,2 , Jean-Michel Grellard 1 , Anaïs Lelaidier 4 ,
Laure Tron 2,3 , Sophie Lefevre Arbogast 1,2,3 , Benedicte Clarisse 1 and Florence Joly 1,2,3

1 Clinical Research Department, Centre François Baclesse, 14000 Caen, France;

[email protected] (M.L.); [email protected] (M.D.S.);
[email protected] (J.-M.G.); [email protected] (S.L.A.);
[email protected] (B.C.); [email protected] (F.J.)
2 Interdisciplinary Research Unit for the Prevention and Treatment of Cancers (ANTICIPE),
National Institute of Health and Medical Research (INSERM), University of Caen Normandie (UNICAEN),
Normandie University, 14000 Caen, France; [email protected]
3 Cancer and Cognition Platform, Ligue Nationale Contre le Cancer, 14000 Caen, France
4 Northwest Data Center (CTD-CNO), Ligue Nationale Contre le Cancer and French National Cancer
Institute (INCa), 14000 Caen, France; [email protected]



* Correspondence: [email protected]; Tel.: +33-2-31-45-86-09; Fax: +33-2-31-45-50-97



Citation: Binarelli, G.; Lange, M.; Simple Summary: Cognitive difficulties and their impact on patients’ quality of life are frequently
Dos Santos, M.; Grellard, J.-M.; reported by patients treated for breast cancer, who ask for support to improve these difficulties.
Lelaidier, A.; Tron, L.; Lefevre Cognitive stimulation and physical activity resulted as beneficial for cognitive difficulties, but they
Arbogast, S.; Clarisse, B.; Joly, F. are challenging to generalize in hospitals. To overcome this limitation, home-based computerized
Multimodal Web-Based Intervention
interventions have been proposed. In this study, the feasibility of a combined intervention of
for Cancer-Related Cognitive
web-based cognitive stimulation and physical activity among breast cancer patients undergoing
Impairment in Breast Cancer Patients:
radiotherapy will be investigated. The overall goal is to develop interventions for cognitive difficulties
Cog-Stim Feasibility Study Protocol.
adapted to supportive care units.
Cancers 2021, 13, 4868. https://
doi.org/10.3390/cancers13194868
Abstract: Cancer-related cognitive impairment (CRCI) is a frequent side-effect of cancer treatment,
Academic Editors: Thomas Licht, with important consequences on patients’ quality of life. Cognitive stimulation and physical activity
Richard Crevenna and Massimo are the most efficient in improving cognitive impairment, but they are challenging to generalize in
Di Maio hospitals’ routine and to patients’ needs and schedules. Moreover, the added value of a combination
of these interventions needs to be more investigated. The Cog-Stim study is an interventional study
Received: 9 July 2021 investigating the feasibility of a web-based multimodal intervention (combining cognitive stimulation
Accepted: 23 September 2021 and physical activity for the improvement of cognitive complaints among breast-cancer patients
Published: 28 September 2021 currently treated with radiotherapy (n = 20). Patients will take part in a 12-week program, proposing
two sessions per week of web-based cognitive stimulation (20 min/session with HappyNeuron® )
Publisher’s Note: MDPI stays neutral
and two sessions per week of web-based physical activity (30 min/session with Mooven® platform).
with regard to jurisdictional claims in
Cognitive complaints (FACT-Cog) and objective cognitive functioning (CNS Vital Signs® ), anxiety,
published maps and institutional affil-
depression (HADS), sleep disorders (ISI) and fatigue (FACIT-Fatigue) will be assessed before and after
iations.
the intervention. The primary endpoint is the adherence rate to the intervention program. Patients’
satisfaction, reasons for non-attrition and non-adherence to the program will also be assessed. The
overall goal of this study is to collect information to develop web-based interventions for cognitive
difficulties in supportive care units.
Copyright: © 2021 by the authors.
Licensee MDPI, Basel, Switzerland.
Keywords: cancer-related cognitive impairment; web-based interventions; multimodal interventions;
This article is an open access article
breast cancer; physical activity; cognitive stimulation
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).

Cancers 2021, 13, 4868. https://doi.org/10.3390/cancers13194868 https://www.mdpi.com/journal/cancers

Cancers 2021, 13, 4868 2 of 14

1. Introduction
Cancer-related cognitive impairment (CRCI) is one of the most frequent side-effects
of cancer and its treatments [1–5]. The impact of chemotherapy on cognition is the most
documented in the literature [1]. However, studies show that radiation therapy and hor-
mone therapy can also affect cognition [6,7]. However, 20% to 30% of patients were shown
to experiment CRCI even before adjuvant treatment [8]. Furthermore, breast cancer pa-
tients had more objective cognitive impairment before any treatment (including breast
cancer surgery), compared with healthy controls [9]. Patients treated for cancer frequently
report (40–75%) having trouble in remembering, thinking, concentrating or finding the
right words [2,10,11]. These symptoms can persist even 10 to 20 years after breast cancer
chemotherapy [12,13] and the repercussions are so profound that they perceive them-
selves as “chemobrain victims” [14]. Indeed, these symptoms impact patients’ quality
of life [15–17], disrupt their return to work [18] and lead to a decrease in self-confidence
at work or in social relationships [15,19–21]. For example, in interviews conducted one
year after breast cancer treatment, survivors reported deterioration in quality of life and
daily functioning due to cognitive difficulties, as well as coping strategies implemented
to manage their work and social life [15]. Some patients also reported that cognitive im-
pairment was the most troublesome symptom after treatment. In addition, approximately
6 years after chemotherapy, patients in remission from breast cancer found that cognitive
difficulties were frustrating and affected their self-confidence and social relationships [21].
Half of these women reported working harder to complete tasks and using compensatory
strategies to complete tasks at work [21]. Because these symptoms can occur before or
during cancer-treatment, it seems crucial to intervene during medical treatment, to alleviate
their impact on patients’ quality of life and to help them gain self-esteem before returning
to work. Moreover, as suggested by Lonkhuizen et al. [22], an early intervention could
prevent or delay worsening of CRCI, resulting in a better long-term efficacy. To date, there
are still no available and validated guidelines for the management of cognitive complaints.
The majority of cancer survivors reporting CRCI (75%) would like to receive support,
especially cognitive stimulation (72%) combined or not with physical activity [2].
Different methods have been evaluated and preliminary findings have shown benefi-
cial effects of non-pharmacological approaches [23]. Among these, cognitive stimulation
and physical activity are especially promising for the improvement of cognitive complaints
and quality-of-life of cancer patients [2,22,24–26].
Nevertheless, further high-quality studies are needed to identify the best efficient
approach between these interventions. Indeed, to date, the efficacy of either cognitive
stimulation or physical activity has been only compared to “standard care” (“standard
group” or “wait-list” group only). Therefore, comparative studies are needed to identify
the best possible intervention.
Furthermore, the intervention, whatever its modality, has been proposed mostly to
survivors a long time after the start of symptoms, and few of these studies evaluated
adherence ratings in the different groups of interventions.
The possible cognitive enhancing effects of a combination of physical activity and
cognitive stimulation have been suggested by several authors. Indeed, it seems that both
interventions can increase neuroplasticity and processes related to cognition and associative
learning, but via different neuronal mechanisms [27,28]. Fissler et al. (2013) [28] proposed
the model “guided plasticity facilitation” in which they suggest physical activity to be
the “plasticity facilitator” because it facilitates synaptic plasticity and neurogenesis, while
cognitive training regulates (guides) synapse formation and elimination [29].
This hypothesis has been confirmed by several studies outside oncology re-
search, [27,28,30–35] although, in the field of CRCI, to our knowledge, only two small
(10 and 28 patients, respectively) studies, with low statistical power, have reported some
preliminary results on the potential effect of a computer-based intervention combining cog-
nitive stimulation and physical activity [36,37]. In both studies, the intervention consisted
of 12 weeks of computer-based cognitive training; aerobic training, or a combination of
Cancers 2021, 13, 4868 3 of 14

both cognitive and aerobic training followed by flexibility (30 min-stretching). In both stud-
ies, the control group performed a 30-min flexibility training. The combined intervention
was done on a Motion Fitness Brain-Bike, on which it was possible to do cognitive and
physical exercises at the same time. The electric bicycle was equipped with a screen on
which patients did cognitive exercises while pedaling. In neither study did the combined
intervention lead to a significant increase in cognition. Authors suggested that the absence
of significant beneficial effects could be a result of the high level of difficulty and stress
reported among patients included in the combined intervention group. Results from these
studies differ from previous results from studies investigating the efficacy of simultaneous
combined intervention in other populations [28,32,38]. It can be suspected that the mode
of intervention in these two studies was too overwhelming and stressful for patients so
that it could result with beneficial effects on cognition.
The setup of such multimodal interventions in standard supportive care is difficult,
due to structural or health system-related barriers (such as cost and lack of trained health-
care providers). Such programs are also not adapted to patients’ schedule and needs (e.g.,
patients had to return frequently to the care center for the center’s sessions in addition to
their doctor’s appointments). E-Health approaches represent one solution to overcome
these barriers because it allows home-based and remotely supervised interventions. The
potential of such approaches has already been shown in multiple domains of mental
health [39–42] and also for the improvement of quality of life [43] and CRCI in cancer pa-
tients [44–50]. Furthermore, e-Health interventions have been shown to improve patients’
engagement [51] and to promote physical activity [52]. However, patients’ acceptance and
easiness in the use of computerized interventions, and their opinion concerning the length
of the program and frequency and length of the sessions is still unclear.
In conclusion, while previous studies have enlightened the interest of using a com-
puterized multimodal intervention, combining cognitive stimulation and physical activity,
it is imperative to investigate further the feasibility and acceptability of a computerized
multimodal intervention, before exploring their efficacy for cognitive improvement in
randomized controlled studies. Thus, in this pilot study, we aim to bridge this gap, investi-
gating the feasibility and acceptability of a program proposing a web-based multimodal
intervention combining cognitive stimulation and adapted physical activity (APA) to breast
cancer patients undergoing radiotherapy who have cognitive complaints.

2. Materials and Methods

2.1. Study design
The Cog-Stim study is a feasibility interventional study conducted in the Cancer
Comprehensive Center of Caen (Caen, France).
Several meta-analysis aiming at evaluating the efficacy of combined interventions
reported better efficacy in interventions with less than five sessions per week, with short
(<45 min) or medium (45 to 60 min) duration per session [32,38]. Conversely, the length of
the intervention was not shown to impact on the efficacy of the combined intervention.
Based on these findings and considering the design of previous studies on combined
interventions in oncology [36,37], we designed a 12-week program combining web-based
cognitive stimulation (2 sessions per week, 20 min per session) and APA (2 sessions per
week, 30 min per session). The program will be proposed to breast cancer patients reporting
cognitive complaints and undergoing adjuvant radiotherapy. Participants will be assessed
pre-intervention (T0) and post-intervention (T1) (Figure 1).

2.2. Objectives
2.2.1. Primary Outcome
The main objective of the Cog-Stim study is to evaluate adherence of breast cancer
patients with cognitive complaints undergoing radiotherapy to a 12-weeks intervention
combining web-based cognitive stimulation and web-based adapted physical activity.
A patient will be considered as adherent to the 12-weeks intervention if 70% of the planned
Cancers 2021, 13, 4868 4 of 14

sessions or more are realized. A session will be considered performed if at least 70% of the
Cancers 2021, 13, 4868 4 of 14
session has been completed.

Figure
Figure 1.
1. Study
Study flowchart.
flowchart. APA:
APA: adapted
adapted physical
physical activity.
activity.

2.2. Objectives
2.2.2. Secondary Outcomes
2.2.1.Secondary
Primary Outcome
objectives are:
(1) The main objective
To evaluate of the Cog‐Stim
the proportion study (attrition)
of acceptance is to evaluate adherence
of the study amongof breast cancer
breast can-
patients
cer with cognitive
patients complaints
starting adjuvantundergoing
radiotherapy, radiotherapy
and accordingto a 12‐weeks
to previous intervention
adjuvant
combining web‐based
chemotherapy. Thecognitive
numberstimulation and web‐based
of patients contacted, adapted
program physical
rejection activity. A
and acceptance
patient will as
rates, bewell
considered as adherent
as reasons to thewill
for rejection 12‐weeks intervention
be recorded, along if 70%the
with of the planned
presence or
sessions or more
absence are realized.
of prior A session
chemotherapy will be considered performed if at least 70% of the
treatment.
session
(2) Tohas been completed.
evaluate patients’ satisfaction regarding the proposed intervention program (fre-
quency, duration, content of the sessions, whether the moment to initiate cognitive
2.2.2. rehabilitation
Secondary Outcomesthroughout the oncologic management is appropriate, obstacles to ac-
cess and use
Secondary the different
objectives are: software, and the perceived usefulness of the program).
This(1)
information will
To evaluate the be proportion
collected using a 13-item questionnaire,
of acceptance (attrition) of thedeveloped in our
study among
institution for this study.
breast cancer patients starting adjuvant radiotherapy, and according to pre‐
(3) To identify viousbarriers
adjuvant to accessing the program
chemotherapy. The number(impossibility
of patientsor contacted,
inability toprogram
use the
computer, no access to internet connections etc.) or to achieve its completion
rejection and acceptance rates, as well as reasons for rejection will be rec‐ (motives
orded, along with the presence or absence of prior chemotherapy treatment.
(2) To evaluate patients’ satisfaction regarding the proposed intervention pro‐
gram (frequency, duration, content of the sessions, whether the moment to
Cancers 2021, 13, 4868 5 of 14

of non-eligibility, non-participation, and drop-out, etc.). This information will be

collected and stored by the neuropsychologist throughout the research program;
(4) To evaluate exercise intensity and training burden and its possible impact on adher-
ence to the protocol. This information will be collected by the APA specialist and
stored on the Mooven App.
These secondary objectives will enable us to identify potential limitations of the
program and to consider adjustments to improve and optimize the study design to develop
a randomized control trial with web-based multimodal intervention.
Furthermore, the pre-post intervention of cognitive complaints, cognitive objective
functioning, anxiety, depression, sleep disorder and fatigue will be assessed.

2.3. Participants: Recruitment and Procedure

This feasibility study aims to recruit 20 patients with breast cancer, reporting sig-
nificant cognitive complaints related to cancer and its treatments and undergoing radio-
therapy. Patients will be enrolled while undergoing radiotherapy treatment, in order
to assess the feasibility of an early combined intervention during medical care. All pa-
tients will give their written informed consent to the study which was approved by the
local ethics committee [Ref. 2019-67, Comité de protection des personnes Nord Ouest
III, France]. This trial is registered as ID RCB 2019-A02500-57, clinical trial NCT04213365
(https://clinicaltrials.gov/ct2/show/NCT04213365?term=cog+stim&draw=2&rank=1,
accessed on 27 Janunary 2021).

2.4. Inclusion Criteria

Patients will be included if they meet all the following criteria: (1) breast cancer
patient aged 18 or more; (2) undergoing adjuvant radiotherapy, independently of pre-
vious chemotherapy but before any hormone therapy treatment; (3) reporting cognitive
complaints with significant impact on their quality of life (quality of life subscale of the
Functional Assessment of Cancer Therapy Cognitive Scale (FACT-Cog) score ≤the 10th
percentile, according to age [53]); (4) absence of any major cognitive dysfunction that could
prevent the patient from achieving the neuropsychological testing (threshold based on
Montreal Cognitive Assessment (MoCA) score [54], according for patient’s age and educa-
tional level, GRECOGVASC normative data [55]); (5) absence of personality disorder or any
other known progressive psychiatric pathology (e.g., schizophrenia); (6) absence of neuro-
logical antecedent (neurological sequelae of brain injury, stroke with loss of consciousness
>30 min, multiple sclerosis, epilepsy, neurodegenerative pathology, etc.); (7) patient having
completed at least an educational level of “end of primary school”; (8) patient with an
access to a functional laptop/computer with a keyboard, headphones or speakers, internet
connection and an e-mail account-being able to use those tools alone; (9) fluent in French;
(10) having signed the informed consent to participate in the study.
Participants who fulfil any of the following criteria will not be included in this study:
(1) excessive alcohol intake or drug use (according to medical record since frequency of
alcohol and drug intake is collected in routine hospital practice during medical manage-
ment of patients); (2) major visual and/or hearing deficit; (3) patient who might not be able
to complete neuropsychological testing; (4) medical contraindication to adapted physical
activity; (5) refusal to participate; (6) patient deprived of liberty or under guardianship;
(7) patient who might not be able to participate due to geographic, social or psychopatho-
logical reasons (patients living in rural areas with a poor internet connection, absence of
time, poor physical or mental conditions etc.).

2.5. Assessments
The baseline assessment (T0), before participating in the intervention program, will be
performed by a neuropsychologist in the Cancer Comprehensive center and the follow-up
assessment after the 3-month intervention program (T1), on-site or at home, based on the
patient’s preference. The MoCA test will be performed at baseline (inclusion criteria).
Cancers 2021, 13, 4868 6 of 14

Objective cognitive function will be assessed at T0 and T1 with the computerized

neurocognitive test battery CNS Vital Sign [56]. This battery uses computerized forms of
traditional tests such as symbol digit coding, the Stroop test and finger tapping and has
also the capacity to automatically quantify “speed factor” via multiple parameters such as
reaction time, psychomotor speed and processing speed. Test-retest reliability, concurrent
validity with traditional tests and discriminant validity was assessed and showed similar
characteristics to the traditional neuropsychological tests [56]. In this study, we will use the
7 main tests of this battery (30 min):
• Verbal Memory (VBM), which investigates word recognition and words memorization
ability (immediate and delayed recall);
• Visual Memory (VIM), which investigates recognition and memorization of geometric
shapes (immediate and delayed recall);
• Finger Tapping (FTT), for motor speed and fine motor control assessment;
• Symbol Digit (SDC) to investigate information processing speed, complex attention,
visual-perceptual speed and complex information processing speed-accuracy;
• Stroop test (ST) for simple and complex reaction time, inhibition/disinhibition abilities,
processing speed and frontal or executive skills assessment;
• Shifting Attention (SAT) to assess executive functions, decision making and reac-
tion time;
• Continuous Performance (CPT) for sustained attention, impulsivity and choice reac-
tion time.
Subjective cognitive complaints will be evaluated at T0 and T1 through the self-report
questionnaire FACT-Cog, which is validated in French, with normative data, and has
4 subscales: Perceived Cognitive Impairments (PCI), Impact on Quality of Life (QoL),
Comments from Others (Oth), and Perceived Cognitive Abilities (PCA) [53,57].
To explore the potential secondary effects of the intervention, the following will be
assessed at T0 and T1: anxiety and depression will be assessed with the Hospital Anxiety
and Depression Scale (HADS) [58], fatigue with the Functional Assessment of Chronic
Illness Therapy-Fatigue (FACIT-Fatigue) [59], and quality of sleep with the Insomnia
Severity Index (ISI) [60]. Patients’ satisfaction will be evaluated at T1 through a 13-items
self-report questionnaire developed in our institution for this study. The questionnaire
focuses on patients’ general appreciation on the program; on frequency, difficulty, contents
and length of physical and cognitive sessions; software’s easiness of use; the time of the
proposed study. Each question has 4 possible answers (from not satisfied at all, to very
satisfied) (see Supplementary Material).
Data collection information is summarized in Table 1.

2.6. The Multimodal Web-Based Intervention

All participants will be enrolled in a web-home-based multimodal intervention for
12 weeks and will be asked to perform two 20-min sessions of cognitive stimulation per
week and two 30-min sessions of APA per week (Figure 1).
After inclusion in the study, participants will meet a neuropsychologist who will
introduce and explain to them the 2 online platforms and will give them all the needed
materials. A starter kit will be provided at that moment, including a heart rate monitor
to adapt the activity during the APA sessions as well as a webcam (if necessary) for the
video-conference sessions. This meeting will allow participants to familiarize themselves
with all instruments of the study and with the person with whom they will be in contact
during the study.
Furthermore, an APA specialist will conduct an initial physical activity interview
(45-to-60-min) during which he/she will present the program to the patient and check the
patient’s availability for APA sessions and medical contraindications to adapt the sessions
according to the needs and constraints of the patients.
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Cancers 2021, 13, 4868 8 of 14

2.6.1. Cognitive Stimulation—HappyNeuron Platform®

Cognitive stimulation will be remotely provided with the HAPPYNeuron® PRESCO
online program (https://www.happyneuronpro.com/, accessed on 27 September 2021)
This software has been developed by a neurologist and it is available in 11 languages
allowing a comparison of results between international studies. It has already been used
in several clinical studies, mainly in the psychiatric field, and in a study with breast
cancer patients [47]. This home-based program trains 12 cognitive domains, especially
attention, memory, executive functions and processing speed—which are the most impaired
after cancer treatments [2] and included 41 different exercises and 9 difficulty levels.
This program is particularly appropriate for an interventional study because it allows
a standardized intervention targeting a wide range of cognitive domains impaired by
cancer treatments (Table 2). Moreover, its user-friendly and intuitive interface, along with
its ludic component, may help maintaining patients’ motivation and their adherence to
the program.

Table 2. HappyNeuron® exercises used for cognitive stimulation.

Cognitive Domains Trained Exercises

Words, Where are you?
Elephant Memory
Shapes and Colours
Heraldry
Displaced Characters
Displaced Images
N-Back
Memory (Verbal and Visual)
Around the World in 80 trips
I Remember You!
Restaurant
An American in Paris
Find Your Way!
Chunking
Objects, Where are You?
Towers of Hanoi
Executive functions Basketball in New-York
Hurry for Change!
Pay Attention!
Private Eye!
Attention
Sound Check!
Ancient Writing
Two-Timing
Under Pressure
Information processing speed
Gulf Stream
Catch the Ladybug!
Split words
Embroidery
Secret files
Speak Your Mind!
Language
Decipher
Writing in the Stars
This Story is Full of Blanks!
Which One is Alike?
The Right Count
Logic Countdown
Ready, Steady, Count!
Cancers 2021, 13, 4868 9 of 14

Table 2. Cont.

Cognitive Domains Trained Exercises

Sleight of Hands
Entangled Figures
visuospatial abilities
Point of View
Turn Around and Around

Participants will have access to the training session through a link sent by e-mail and
will have access to it until they receive another mail with the next planned session. All
patients will start with the first difficulty’s level, which will increase accordingly with
their performance during exercises. Patients will reach the next level after two successful
repetitions of the exercise at the given level. Instructions and demonstrations precede each
exercise as well as a test to verify if instructions have been well understood. Automatic
feedback is generated after each exercise to congratulate patients or to encourage them to
persevere if they fail. When starting a new session, patients will carry on at the level they
stopped during the previous session.
The neuropsychologist will have access to patients’ results to estimate the evolution
of their performance and to verify the frequency with which sessions are being completed.
The neuropsychologist also will perform a weekly check for patients’ achievement to the
cognitive stimulation program and in case of non-achievement of two following sessions,
he/she will contact the patient to verify reasons of non-achievement.

2.6.2. Adapted Physical Activity Training—Mooven® Platform

Participants will access adapted physical activity sessions through the online plat-
form “Mooven® ” (https://mooven.app/, accessed on 27 September 2021). It is currently
involved in more than 15 projects, including a trial with cancer patients.
Participants will schedule two 30-min sessions per week with an APA specialist who
will remotely supervise the session through a video-conference system. APA sessions
will be standardized and will consist of a warm-up (5 min), endurance/cardio or muscle-
strengthening activities (20 min) and then stretching (5 min), as recommended by the
French National Cancer Institute [61]. The content of the sessions will be adapted to breast
cancer patients [62,63] and if necessary, to their constraints and medical contraindications.
Patients’ heartbeat will be constantly monitored using a wrist heart rate monitor and data
will be updated in patients’ profile. Furthermore, patients’ rating of perceived exertion will
be measured by the Borg rating of the perceived exertion scale [64]. This scale ranges from
6 (no exertion at all) to 20 (maximal exertion).
Patients will have access to their calendar with the next planned video-conference
sessions. In case of patient’s inability to attend the video call with the APA specialist, the
latter will submit a description of the session to be carried out in autonomy (video supports
or sheets) and will contact them after the session to collect the difficulties encountered by
the patients through a phone-administered questionnaire. The APA specialist will also
report reasons for non-achievement if these do occur.

2.7. Statistical Analysis

For the pilot/feasibility study, the inclusion of 20 patients is needed to meet the
main objective of evaluating adherence of breast cancer patients with cognitive complaints
undergoing radiotherapy to a 12-weeks intervention combining web-based cognitive
stimulation and web-based adapted physical activity. A sample size of 20 patients to be
enrolled (including the augmentation to anticipate a maximum of 10% of patients with
non-evaluable data) will allow estimation with a 95% confidence interval of width +/− 20%
an adherence rate of at least 70%.
We expect to reach an adherence rate of 70% (to the APA sessions and the cognitive
training sessions) in the present study. Completed sessions and duration will be checked
Cancers 2021, 13, 4868 10 of 14

by the neuropsychologist from the patients’ statistics in the HAPPYNeuron® platform

regarding cognitive training. Regarding APA sessions, the APA specialist will collect
the information directly from patients’ feedback after each session and will confront this
self-reported information to those collected by the pedometer (objective measure).
Analysis of non-eligibility motives and factors associated with participation (through
data collected by the neuropsychologist at baseline and the coach during the follow-up) as
well as analysis of the satisfaction questionnaire will enable us to raise potential limitations
of the program such as:
• social barriers (patients living in remote areas with a poor internet connection, patients
with limited access to computer material or low skills in informatics, etc., resulting
in selection bias of more affluent women and social inequalities in the access to
the program),
• technological barriers (patients with limited skills in informatics, inappropriate material),
• or availability barriers (already in an APA or cognitive training program, program
too demanding/exhausting, not available enough to complete it, not the good time
during cancer therapeutic management to propose cognitive management, etc.).
These key elements will be crucial to identify potential improvements and adjustments
of the intervention design for the next steps to develop a randomized study.
Data analysis will be based on the data obtained from the total population (“intent
to treat” analysis) enrolled in the protocol. Exploratory data analyses will provide, for
qualitative variables, the frequencies and their exact 95% confidence interval (binomial law);
for quantitative variables, the mean, the standard deviation of the mean, the median and
the quartiles. The demographic, clinical and biological characteristics of the patients will
be described using the “intention-to-treat” population. Whenever possible, non-parametric
tests will be used. The adherence of breast cancer patients to cognitive stimulation sessions
coupled with adapted physical activity will be described in detail as well as the reasons for
non-acceptance of the study.

3. Discussion
Breast Cancer patients are actively demanding interventions to improve their cancer-
related cognitive impairment [14,65]. Nevertheless, without available and validated guide-
lines for the management of cognitive complaints, only 30% of patients receive the help
demanded for their cognitive impairment [66]. While the beneficial effects of both cognitive
stimulation and physical activity have been proved [2,23–26], many barriers limit the setup
of such interventions in supportive care units in hospitals. Web-based interventions have
been used to reduce some of these barriers, including the cost of interventions, while
increasing convenience for patients, also reaching patients who are normally isolated and
cannot benefit from these interventions [67] and have resulted as efficient in the improve-
ment of CRCI [44–50]. Nevertheless, little is known about patients’ preferences in terms
of length of the program, length, and frequency of the sessions. This pilot study aims to
bridge this gap, collecting patients’ opinion on this topic. Thereafter, based on the results
from this pilot study, a multisite randomized controlled study will be conducted, to identify
the best computerized intervention for the improvement of CRCI.
The web-based/home-based nature of the Cog-Stim study program will allow a
generalization of this intervention for all cancer patients with cognitive complaints. This
will provide better support for cancer patients with cognitive difficulties by helping them go
back more smoothly to daily living activities, social interactions and work, thus improving
their quality of life during and after cancer treatments. The value of such interventions
has also increased with the COVID-19 outbreak, during which, thanks to web-based
approaches, it has been possible to provide remote support.

4. Conclusions
The efficacy of web-based cognitive stimulation and physical activity has been demon-
strated, but the added value of a combination of these interventions needs to be more
Cancers 2021, 13, 4868 11 of 14

investigated. This study will assess the acceptability and feasibility of such combined in-
tervention using web-based platforms in breast cancer patients with cognitive complaints.
The data collected from the Cog-Stim study will be the base for the development of a
personalized combined intervention to help patients to cope with CRCI.

Supplementary Materials: The following are available online at https://www.mdpi.com/article/

10.3390/cancers13194868/s1, Questionnaire.
Author Contributions: Writing—original draft preparation, G.B. and M.L.; writing—review and
editing, F.J., L.T., S.L.A., B.C., A.L., J.-M.G. and M.D.S. All authors have read and agreed to the
published version of the manuscript.
Funding: This work is supported by grants from the French Cancer Institute (INCa) as part as the
call for project “Population health intervention research: Addressing all dimensions of cancer control”
2018 (Ref. RISP19-033_AM, INCA_13703), the French League against cancer (Ligue contre le cancer)
as part as the “Prix Rose sur Green” 2019, the association Géfluc Normandie, the Calvados League
and the doctoral grant RIN 50% 2020. The platform “cancer and cognition” is also supported by
the National League Against Cancer. RIN CancerCOG: This research was supported by Normandy
Region and the European Union. Europe gets involved in Normandy with European Regional
Development Fund (ERDF).
Institutional Review Board Statement: This study received ethical approval from the Medical Ethics
Committee North-West III in December 2019 (Reference 2019-67, N◦ ID-RCB: 2019-A02500-57. All
patients will give their written informed consent before any study-related procedure. The study will
be conducted according to the guidelines of the Declaration of Helsinki.
Informed Consent Statement: Informed consent will be obtained from all subjects involved in
the study.
Data Availability Statement: The data presented in this study are available on request from the
corresponding author. The data are not publicly available accordingly to good clinical practice (GCP)
guidelines.
Conflicts of Interest: The authors declare no conflict of interest.

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