Clinical trial NCT06614647: RESPONSE: Colorectal Cancer Survivors' Follow-up Care - Now Digital and Need-based
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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Colorectal Cancer
Quality of Life
Survivorship
Keywords: Circulating Tumor DNA
Organ-specific late effects
Biopsychosocial Late effects
Lead sponsor: University of Aarhus
Sponsor class: OTHER
Collaborators: name: Aarhus University Hospital
name: Aalborg University Hospital
name: University of Southern Denmark
name: Randers Regional Hospital
name: Viborg Regional Hospital
name: Gødstrup Hospital
name: Odense University Hospital
name: Herlev Hospital
name: Bispebjerg Hospital
name: Sygehus Lillebaelt
name: Svendborg Hospital
First posted: 2024-09-26
Enrollment: 400
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
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

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, 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 \&amp;lt;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\&amp;#39;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\&amp;#39; 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.

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).

Primary outcomes:
measure: Health related Quality of Life (HRQoL)
timeFrame: At 3 and 5 years follow-up.
Secondary outcomes:
measure: Overall survival (OS)
timeFrame: At 3 and 5 years follow-up
measure: Recurrence-free survival (RFS)
timeFrame: At 3 and 5 years follow-up.
measure: HRQoL evaluated by EORTC QLQ-C30 for the five functional scales
timeFrame: At 12 and 36 months.
measure: HRQoL evaluated by EQ-5D-5L - EUROQOL - 5 Dimensions 5 Levels
timeFrame: At 12 and 36 months.
measure: Fear of Cancer Recurrence Inventory score
timeFrame: At 12 and 36 months.
measure: ePROM response rates
timeFrame: From 3 to 36 months.
measure: Health care cost
timeFrame: At 3 and 5 years.
measure: Societal costs
timeFrame: At 3 and 5 years.
measure: Quality-adjusted life years (QALYs)
timeFrame: At 3 and 5 years.
measure: Patient satisfaction
timeFrame: From 3 to 36 months.
measure: Prognostic value of ctDNA
timeFrame: At months 3, 12, 24, and 36 after operation
measure: FACIT Fatigue - Functional Assessment of Chronic Illness Therapy - Fatigue scale
timeFrame: At 12 and 36 months.
measure: Rectal Cancer Pain Score
timeFrame: At 12 and 36 months.
measure: Insomnia severity index (ISI)
timeFrame: At 12 and 36 months.
measure: GAD-7 - General Anxiety Disorder-7
timeFrame: At 12 and 36 months.
measure: PHQ-9 - Patient Health Questionnaire-9
timeFrame: At 12 and 36 months.
measure: LARS score - Low Anterior Resection Syndrome Score
timeFrame: At 12 and 36 months.
measure: Wexner Incontinence Score
timeFrame: At 12 and 36 months.
measure: St. Marks Incontinence Score
timeFrame: At 12 and 36 months.
measure: Bristol Stool Chart
timeFrame: At 12 and 36 months.
measure: Patient Assessment of Constipation Symptoms
timeFrame: At 12 and 36 months.
measure: Colostomy impact score
timeFrame: At 12 and 36 months.
measure: Rectal Cancer Female Sexuality Score (sexually active only)
timeFrame: At 12 and 36 months.
measure: ICIQ - Male/Female Lower Urinary Tract Symptoms
timeFrame: At 12 and 36 months.
measure: ILEF-5 - International Index for Erectile Function
timeFrame: At 12 and 36 months.
Other outcomes:
measure: Comparison of cutting edge ctDNA detection methods in plasma.
timeFrame: At 3 and 5 years.
Locations:
city: Herlev
country: Denmark
facility: Herlev Hospital
state: Capital Region of Denmark
city: Herning
country: Denmark
facility: Gødstrup Hospital
state: Central Denmark Region
city: Randers
country: Denmark
facility: Regional Hospital Randers
state: Central Denmark Region
city: Aalborg
country: Denmark
facility: Aalborg University Hospital
state: North Denmark Region
city: Odense
country: Denmark
facility: Odense University Hospital
state: The Region of Southern Denmark
city: Svendborg
country: Denmark
facility: Svendborg Sygehus
state: The Region of Southern Denmark
city: Aarhus
country: Denmark
facility: Aarhus University Hospital
city: Copenhagen
country: Denmark
facility: Bispebjerg Hospital
city: Horsens
country: Denmark
facility: Regional Hospital Horsens
city: Viborg
country: Denmark
facility: Regional Hospital Viborg
Study officials:
affiliation: University of Aarhus
name: Lene H Iversen, Prof.
role: PRINCIPAL_INVESTIGATOR
affiliation: Aarhus University Hospital
name: Peter Christensen, Prof.
role: PRINCIPAL_INVESTIGATOR
affiliation: Aalborg University Hospital
name: Ole Thorlacius-Ussing, Prof.
role: PRINCIPAL_INVESTIGATOR
affiliation: Aarhus University Hospital
name: Robert Zacchariae, Prof.
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Southern Denmark
name: Liza Sopina, Ass.Prof.
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Aarhus
name: Claus L Andersen, Prof.
role: PRINCIPAL_INVESTIGATOR
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