Trial Title:
RESPONSE: Colorectal Cancer Survivors' Follow-up Care - Now Digital and Need-based
NCT ID:
NCT06614647
Condition:
Colorectal Cancer
Quality of Life
Survivorship
Conditions: Official terms:
Colorectal Neoplasms
Conditions: Keywords:
Circulating Tumor DNA
Organ-specific late effects
Biopsychosocial Late effects
Study type:
Interventional
Study phase:
N/A
Overall status:
Recruiting
Study design:
Allocation:
Non-Randomized
Intervention model:
Parallel Assignment
Intervention model description:
The region of residency determines the allocation to the intervention group or
standard-of-care group. Patients in the intervention group will be stage I-II colorectal
cancer survivors residing in Central Denmark Region and North Denmark Region. Both
regions have fully implemented 'organ-specific late-effects clinics' offering a
standardized patient-centered, interdisciplinary, multiorgan approach and have
implemented the digital platform that supports the smartphone care guide. Patients in the
standard group will be the corresponding patients residing in the remaining Danish
Regions, in which similar standardized late effects clinics and the digital care-guide
framework are not yet implemented.
Primary purpose:
Diagnostic
Masking:
None (Open Label)
Intervention:
Intervention type:
Diagnostic Test
Intervention name:
Recurrence monitoring with circulating tumor DNA (ctDNA) as a high risk biomarker
Description:
IG patients will receive the following intervention at 3, 12, 24, and 36 months
post-surgery:
1) Recurrence risk stratification by ctDNA analysis of blood samples:
a) Only if ctDNA becomes positive, will imaging be performed. b) If ctDNA is positive,
but recurrent disease is not detected by imaging or clinical and endoscopic evaluation,
the patient will be referred back to intensified ctDNA measurements repeated every 4
months until either ctDNA becomes negative or recurrence is confirmed by subsequent
imaging.
Arm group label:
Intervention group (IG)
Intervention type:
Behavioral
Intervention name:
Monitoring for late adverse effects with electronic patient reported outcome measures (ePROMs)
Description:
2) Collection and analyses of ePROMs to identify whether patients suffer from
organ-specific late effects or biopsychosocial late effects and monitor of health
related quality of life and the impact of late adverse effects hereon.
Arm group label:
Intervention group (IG)
Intervention type:
Behavioral
Intervention name:
Systematic treatment of organ-specific late effects and/or biopsychosocial late effects
Description:
3) When needed, standardized treatment for organ-specific late effects according to
newly published national guidelines at specialized centers. Further, online
cognitive behavioral therapy is offered to patients suffering from severe
biopsychosocial late effects.
Arm group label:
Intervention group (IG)
Intervention type:
Behavioral
Intervention name:
Digital care-guide for long-term follow-up after cancer treatment
Description:
Use of a digital care-guide from study inclusion to guide the patient trough the
follow-up program, in the form of a personalized smart phone app.
Arm group label:
Intervention group (IG)
Summary:
Over the last decades, the 3-year recurrence rates for patients with stage I and II
colorectal cancer have decreased to just 5% and 12%. The follow-up program offered to
stage I and low-risk stage II patients has not changed accordingly and is still focused
solely on recurrence detection. Moreover, it is a one-size-fits-all program, i.e. most of
the follow-up resources are spent on non-recurrence patients who do not benefit.
Up to 50% of cancer survivors suffer from reduced quality of life related to fear of
cancer recurrence, treatment-related psychological distress, and/or severe late adverse
effects of a biopsychosocial and/or organ-specific origin. Today many of these symptoms
can be treated effectively. However, no systematic program aimed at monitoring and
addressing the symptoms has been implemented yet.
The current project is testing a newly developed, digitally managed, patient-centered
follow-up program that focuses on individual patient needs, including fear of cancer
recurrence, psychological well-being, management of late adverse effects, and recurrence
surveillance. This new program will be compared to the current standard of care in a
national network of 11 colorectal cancer surgical centers in four of five Danish regions.
Patients in the intervention group will receive the following:
1. Risk-stratified circulating tumor DNA (ctDNA) guided recurrence surveillance.
2. Late adverse effects monitoring with electronic patient-reported outcome measures,
which are validated questionnaires that can identify and qualify late adverse
effects.
3. Systematic treatment for organ-specific and/or biopsychosocial late adverse effects.
4. A digital care guide, to support the patient trajectory through the follow-up
program, as a smartphone app.
Patients in the standard group will receive standard-of-care follow-up.
The primary study endpoint will be the difference in health-related quality of life
between the intervention and standard group. Secondary outcomes include e.g., comparison
of health-related costs, differences in fear of cancer recurrence, recurrence-free
survival, and patient satisfaction.
The investigators expect the new follow-up program to be better than the standard-of-care
program in terms of the primary endpoint - quality of life - without compromising
recurrence detection, and without increasing costs.
Detailed description:
Background:
Colorectal cancer (CRC) screening was implemented in Denmark in 2014 and has effectively
shifted the CRC stage at the time of diagnosis from late stage (III and IV) to earlier
stages (I and II)[1]. Consequently, more patients are offered curative intended
treatment, which increases the number of survivors in postoperative follow-up care: In
2020, 65% of Danish patients with CRC, potentially eligible for follow-up care, had stage
I-II disease[1].
The current follow-up for CRC survivors is recurrence-focused, with computed tomography
(CT) imaging at 12 and 36 months[2] as early recurrence detection is critical to increase
the possibility of curative treatment: The 5-year survival rate for patients treated for
recurrence with curative intent is ~40% compared to <10% for patients managed with
palliative or best supportive care[3-6]. However, the risk of recurrence strongly depends
on the CRC stage: The 3-year cumulative recurrence rate is only 4.5%-7.9% for stage I and
10%-16% for stage II[7-9]. Consequently, the resources allocated to CRC follow-up in
Denmark are primarily dissipated on patients who will never experience a recurrence.
Hence, the challenge remains to distinguish between high- and low-risk patients, i.e.,
tailor the follow-up program to the personal risk of recurrence instead of
"one-size-fits-all".
A promising and novel surveillance method for CRC recurrence is to screen longitudinally
collected blood samples for the presence of circulating tumor DNA (ctDNA). Serial ctDNA
analyses detect recurrence with high sensitivity (88%) and specificity (97%) independent
of the stage (hazard ratio (HR)=40.7; 95% confidence interval (CI): 11.6-143) and with a
median lead-time of 7-10 months compared to current standard-of-care follow-up[10-13].
Thus, serial ctDNA analyses have the potential to efficiently identify the 4.5%-16% of
stage I-II patients, who should be offered CT imaging, whereas the remaining 84-95% of
patients are spared unnecessary CT imaging.
CRC survivors with a low risk of recurrence may perceive other challenges than CRC
recurrence as equally or more important in everyday life. Such challenges may include the
psychological distress related to the CRC diagnosis, exaggerated fear of cancer
recurrence (FCR) regardless of the actual risk of recurrence, and the presence of
treatment-related organ-specific late effects, which may negatively impact their quality
of life (QoL). Independently of stage, 13% of patients with CRC report persistently low
QoL and/or high levels of psychological distress, e.g., impaired emotional well-being
and/or high FCR[14].
Approximately half of CRC survivors suffer from organ-specific late effects, e.g., bowel,
urinary, or sexual dysfunction[15-18]. In a recent study, 20% of colon cancer patients
and 30% of rectal cancer patients expressed a wish for help managing their organ-specific
late effects[19]. Besides organ-specific late effects, many CRC survivors experience one
or more persistent general symptoms and late effects after their cancer treatment
including psychological distress, depression, anxiety, insomnia, fatigue, pain, and
impaired cognitive function. While the management of these so-called biopsychosocial late
effects has received only little attention until recently, a growing body of evidence
suggests that these issues can be treated effectively with cognitive behavioral
approaches[20-24]. However, none of these challenges are addressed by today's
recommended follow-up care program.
To improve the management of follow-up care, recent studies have demonstrated the benefit
of high patient satisfaction with electronic Patient-Reported Outcome Measures
(ePROMs)[25]. Furthermore, it has been shown that 80% of Danish patients with CRC respond
to ePROMs and that those with organ-specific late effects and/or biopsychosocial late
effects can effectively be identified using ePROMs[19]. Hence, ePROMs have the potential
to help clinicians stratify CRC survivors to postoperative surveillance or interventions
for treating both organ-specific late effects and biopsychosocial late effects.
New technology further facilitates the management of follow-up care: the use of digital
care-guides has become increasingly popular in the Danish Health care system. One example
is a framework based on a smartphone app that enables implementation of a comprehensive
digital care guide in the follow-up program for CRC (Emento)[26]. This app can help
maintain patient autonomy, acting as both a reference work and a timed tool to inform,
educate, and guide the patient through the follow-up program.
RESPONSE proposes to use each of the elements described above in a new, individualized
follow-up program for CRC. All elements have already been tested and have shown their
great potential in separate efficacy trials[11-13,19,23,25]. However, the impact of
combining all four elements in a single follow-up program has never previously been
investigated.
Aim:
The overall aim of this study was to investigate whether the combination of the above
elements in recurrence surveillance, could improve health-related QoL (HRQoL), without
compromising overall survival (OS) and recurrence-free survival (RFS) or increasing
costs. Thus, our study objective was to design a surveillance program fulfilling these
criteria. Further, the objective was to conduct a trial where this program could be
compared to standard-of-care recurrence surveillance.
The new follow-up program includes: 1) serial ctDNA monitoring to identify individuals
with high risk of recurrence, 2) serial ePROMs monitoring to identify 'organ-specific
late effects' and 'biopsychosocial late effects', 3) planned and systematic
management/intervention of recurrence and late effects, and 4) personalized self-managed
follow-up by a digital care guide as a smartphone application.
Study design:
This new program will be compared to the standard-of-care imaging-based recurrence
surveillance in a Danish multicenter, interventional effectiveness trial, including 392
patients from 11 surgical centers. The patients will be divided into two arms: the
intervention group (IG) and the standard-of-care group (SG).
IG patients (n=196) will receive all the following at 3-,12-,24-, and 36-months
post-surgery:
1. Recurrence risk stratification by plasma ctDNA.
1. If ctDNA becomes positive, CT imaging of the thorax and abdomen will be
performed. This enables the CT imaging resources to be directed at the
high-risk individuals (=ctDNA positive) only.
2. The results of the CT imaging are discussed at the usual MDT at the responsible
surgical department, where pathologists, oncologists, CRC surgeons, and
radiologists are present. The MDT decides whether further diagnostic
initiatives should be taken, e.g., endoscopy or further imaging.
3. If recurrent disease is detected, the patient is treated according to the
national Danish guidelines, and the outcome is registered in the RESPONSE
trial.
4. If a recurrence is NOT detected by imaging or subsequent clinical examinations,
the patient returns to the RESPONSE trial with increased ctDNA testing
frequency every four months.
5. If longitudinal ctDNA tests become negative, the patient returns to the default
ctDNA test frequency.
6. If longitudinal ctDNA tests are repeatedly positive, CT imaging will be
prompted and discussed at MDT until a site of recurrence can be confirmed.
2. Personalized self-managed follow-up care, using a digital platform with longitudinal
collection of ePROMs to identify
1. whether patients suffer from organ-specific late effects and/or biopsychosocial
late effects
2. whether this impacts patients' overall HRQoL.
3. Intervention for organ-specific late effects and/or biopsychosocial late effects if
needed.
SG patients (n=196) will receive standard follow-up with CT imaging at 12- and 36-months
post-surgery, at the surgical departments according to Danish national guidelines. Any
local variation/addition to the standard follow-up program will be allowed.
All SG patients will have longitudinal blood samples collected at the same time points as
IG patients but only analyzed after the end of the trial, to enable comparison of ctDNA
vs. CT imaging as a recurrence predictor. Furthermore, SG patients will receive similar
ePROMs as IG patients to collect information at the same time points. However, these will
only be analyzed after the end of the trial.
Outcomes and power calculation:
The primary study outcome will be the difference in HRQoL between groups. This will be
calculated as the difference in EORTC-QLQ-C30 (global health/QoL domain) between IG and
SG at 36 months.
A mean global score of 61 points in the SG is assumed. A score difference of 7 or more
between groups will be considered as the minimal clinical important difference (MID).
Thus, 170 patients are required in each group to detect an increase of 7 for a mean
global score of 68 in the IG with 80% power and 5% significance level. Expecting a
drop-out rate of 10%, 189 patients need to be included in each group.
For the secondary objective, OS and RFS, the difference in cumulative RFS and OS between
groups will be calculated at 3 and 5 years. Expectantly the cumulative RFS will be 93% in
the SG and 92% in the IG. With 196 patients in each group, a decrease in RFS of 9% in IG
can be shown with 80% power at a 5% significance level. Thus, the number of included
patients is increased to 196 in each group. Non-inferiority will be declared if the
difference in RFS is within this limit. The mean OS in the groups is expectantly 77,5%.
With 196 patients in each group, an increase of 10% in OS for the IG can be shown with
70% power at a 5% significance level.
Data analyses and statistics:
All data will be presented using descriptive statistics. The ePROM scores will be
calculated according to the scoring guidelines for each of the questionnaires. Missing
PRO data in form of missing items within an ePROM assessment will be imputed according to
the questionnaire's scoring guideline.
The incremental cost-effectiveness ratio (ICER) will be calculated as ∆cost/∆effect. QALY
will be calculated as life expectancy x HRQoL, as determined by the Danish value set for
EQ-5D-5L. Kaplan-Meier estimates will be used for the estimation of median times to
clinical recurrence, disease, or death, and their confidence intervals stratified
according to follow-up intensity. The difference in clinical recurrence versus molecular
recurrence will be compared using paired t-tests and regression analyses.
Data will be analyzed as intention-to-treat and per-protocol. Interim analyses will be
made when 50% of patients in each group have been included, and when 100% in each group
have been included and have completed a one-year follow-up.
Quality insurance and ethics:
Data completeness and quality will be monitored by the RESPONSE steering committee, and
The General Data Protection Regulation, the Danish Data Protection Act, the Health Act,
and the Helsinki II declaration will be complied with unconditionally.
The results of the RESPONSE study are expected to be published in international
scientific journals. The reporting will follow the CONSORT guidelines for reporting
randomized controlled trials.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
1. Patients treated for stage I and low risk stage II colorectal cancer with curative
intend.
2. Age 18 years or older.
3. Understands spoken and written Danish language.
4. Able to use digital care-guide as smartphone application.
5. The patient is also included in DANISH.MRD part 1.
Exclusion Criteria:
1. Patients who are unlikely to comply with the protocol, unable to return for
subsequent visits and/or otherwise considered by the PIs to be unlikely to complete
the study.
2. Patients who are not able or willing to adhere to the digital platform.
3. Patients treated only with local endoscopic resection, e.g.,Transanal Endoscopic
microsurgery (TEM).
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Herlev Hospital
Address:
City:
Herlev
Zip:
2730
Country:
Denmark
Status:
Not yet recruiting
Contact:
Last name:
Mads F Klein, MD, Ph.D
Email:
mads.falk.klein@regionh.dk
Contact backup:
Last name:
Jeppe Kildsig, MD
Email:
Jeppe.Kildsig@regionh.dk
Facility:
Name:
Gødstrup Hospital
Address:
City:
Herning
Zip:
7400
Country:
Denmark
Status:
Not yet recruiting
Contact:
Last name:
Claudia Jaensch, MD, PhD
Email:
Claudia.Jaensch@goedstrup.rm.dk
Facility:
Name:
Regional Hospital Randers
Address:
City:
Randers
Zip:
8930
Country:
Denmark
Status:
Recruiting
Contact:
Last name:
Peter Bondeven, MD, PhD
Email:
petefred@rm.dk
Facility:
Name:
Aalborg University Hospital
Address:
City:
Aalborg
Zip:
9000
Country:
Denmark
Status:
Not yet recruiting
Contact:
Last name:
Ole Thorlacius-Ussing, MD, PhD
Email:
otu@rn.dk
Facility:
Name:
Odense University Hospital
Address:
City:
Odense
Zip:
5000
Country:
Denmark
Status:
Recruiting
Contact:
Last name:
Per Vadgaard Andersen, MD, PhD
Email:
Per.vadgaard.andersen@rsyd.dk
Facility:
Name:
Svendborg Sygehus
Address:
City:
Svendborg
Zip:
5700
Country:
Denmark
Status:
Recruiting
Contact:
Last name:
Per Vadgaard Andersen, MD, PhD
Email:
Per.vadgaard.andersen@rsyd.dk
Facility:
Name:
Aarhus University Hospital
Address:
City:
Aarhus
Zip:
8000
Country:
Denmark
Status:
Not yet recruiting
Contact:
Last name:
Lene H Iversen, MD, PhD
Email:
lene.h.iversen@dadlnet.dk
Facility:
Name:
Bispebjerg Hospital
Address:
City:
Copenhagen
Zip:
2400
Country:
Denmark
Status:
Not yet recruiting
Contact:
Last name:
Nis Hallundbæk Schlesinger
Email:
Nis.Hallundbaek.Schlesinger@regionh.dk
Facility:
Name:
Regional Hospital Horsens
Address:
City:
Horsens
Zip:
8700
Country:
Denmark
Status:
Recruiting
Contact:
Last name:
Kåre Gotschalck, MD, Ph.D
Email:
kaarsune@rm.dk
Facility:
Name:
Regional Hospital Viborg
Address:
City:
Viborg
Zip:
8800
Country:
Denmark
Status:
Recruiting
Contact:
Last name:
Anders Tøttrup, MD, PhD
Email:
uffescho@rm.dk
Start date:
September 15, 2024
Completion date:
February 1, 2030
Lead sponsor:
Agency:
University of Aarhus
Agency class:
Other
Collaborator:
Agency:
Aarhus University Hospital
Agency class:
Other
Collaborator:
Agency:
Aalborg University Hospital
Agency class:
Other
Collaborator:
Agency:
University of Southern Denmark
Agency class:
Other
Collaborator:
Agency:
Randers Regional Hospital
Agency class:
Other
Collaborator:
Agency:
Viborg Regional Hospital
Agency class:
Other
Collaborator:
Agency:
Gødstrup Hospital
Agency class:
Other
Collaborator:
Agency:
Odense University Hospital
Agency class:
Other
Collaborator:
Agency:
Herlev Hospital
Agency class:
Other
Collaborator:
Agency:
Bispebjerg Hospital
Agency class:
Other
Collaborator:
Agency:
Sygehus Lillebaelt
Agency class:
Other
Collaborator:
Agency:
Svendborg Hospital
Agency class:
Other
Source:
University of Aarhus
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06614647
