Ignite Creation Date:
2024-10-25 @ 7:55 PM
Last Modification Date:
2024-10-26 @ 3:41 PM
Study NCT ID:
NCT06614647
Status:
RECRUITING
Last Update Posted:
None
First Post:
2024-07-09
Brief Title:
RESPONSE Colorectal Cancer Survivors Follow-up Care - Now Digital and Need-based
Sponsor:
None
Organization:
None
Study Overview
Official Title:
RESPONSE Colorectal Cancer Survivors Follow-up Care - Now Digital and Need-based A National Interventional Effectiveness Trial for Stage I and II Patients
Status:
RECRUITING
Status Verified Date:
2024-09
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
No
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
RESPONSE
Brief 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 ie 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 andor severe late adverse effects of a biopsychosocial andor 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 andor 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 eg 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
Up to 50 of cancer survivors suffer from reduced quality of life related to fear of cancer recurrence treatment-related psychological distress andor severe late adverse effects of a biopsychosocial andor 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 andor 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 eg 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 II1 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 disease1
The current follow-up for CRC survivors is recurrence-focused with computed tomography CT imaging at 12 and 36 months2 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 amplt10 for patients managed with palliative or best supportive care3-6 However the risk of recurrence strongly depends on the CRC stage The 3-year cumulative recurrence rate is only 45-79 for stage I and 10-16 for stage II7-9 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 ie 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 HR407 95 confidence interval CI 116-143 and with a median lead-time of 7-10 months compared to current standard-of-care follow-up10-13 Thus serial ctDNA analyses have the potential to efficiently identify the 45-16 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 andor high levels of psychological distress eg impaired emotional well-being andor high FCR14
Approximately half of CRC survivors suffer from organ-specific late effects eg bowel urinary or sexual dysfunction15-18 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 effects19 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 approaches20-24 However none of these challenges are addressed by todayamp39s 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 ePROMs25 Furthermore it has been shown that 80 of Danish patients with CRC respond to ePROMs and that those with organ-specific late effects andor biopsychosocial late effects can effectively be identified using ePROMs19 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 Emento26 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 trials11-13192325 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 managementintervention 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 n196 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 eg 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 andor biopsychosocial late effects
2 whether this impacts patientsamp39 overall HRQoL
3 Intervention for organ-specific late effects andor biopsychosocial late effects if needed
SG patients n196 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 variationaddition 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 healthQoL 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 775 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 questionnaires scoring guideline
The incremental cost-effectiveness ratio ICER will be calculated as costeffect 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
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 II1 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 disease1
The current follow-up for CRC survivors is recurrence-focused with computed tomography CT imaging at 12 and 36 months2 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 amplt10 for patients managed with palliative or best supportive care3-6 However the risk of recurrence strongly depends on the CRC stage The 3-year cumulative recurrence rate is only 45-79 for stage I and 10-16 for stage II7-9 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 ie 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 HR407 95 confidence interval CI 116-143 and with a median lead-time of 7-10 months compared to current standard-of-care follow-up10-13 Thus serial ctDNA analyses have the potential to efficiently identify the 45-16 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 andor high levels of psychological distress eg impaired emotional well-being andor high FCR14
Approximately half of CRC survivors suffer from organ-specific late effects eg bowel urinary or sexual dysfunction15-18 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 effects19 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 approaches20-24 However none of these challenges are addressed by todayamp39s 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 ePROMs25 Furthermore it has been shown that 80 of Danish patients with CRC respond to ePROMs and that those with organ-specific late effects andor biopsychosocial late effects can effectively be identified using ePROMs19 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 Emento26 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 trials11-13192325 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 managementintervention 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 n196 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 eg 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 andor biopsychosocial late effects
2 whether this impacts patientsamp39 overall HRQoL
3 Intervention for organ-specific late effects andor biopsychosocial late effects if needed
SG patients n196 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 variationaddition 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 healthQoL 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 775 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 questionnaires scoring guideline
The incremental cost-effectiveness ratio ICER will be calculated as costeffect 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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None