Recurrent Disease Detection After Resection of Pancreatic Adenocarcinoma Using a Standardized Surveillance Strategy

Study Overview
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Brief Summary
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A randomized controlled trial, nested within an existing prospective cohort (Dutch Pancreatic Cancer Project; PACAP) according to the 'trials within cohorts' (TwiCs) design in which the effect of a standardized surveillance, with serial tumor marker testing and routine imaging, compared to current non-standardized practice, on overall survival and quality of life in patients with primary resected PDAC is investigated. The most important secondary endpoint is quality of life. Other secondary endpoints are clinical and radiological patterns of PDAC recurrence, the compliance of patients to our standardized follow-up strategy, the impact of a standardized surveillance on (eligibility for) additional treatment, and the tolerance of additional treatment. The need for this clinical trial is emphasized by the the emergence of more potent local and more effective systemic treatments for PDAC recurrence, leading to a rising interest in early diagnosis by a standardized approach to follow-up with routine imaging and serial serum tumor marker testing.

Detailed Description
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Rationale: Radical resection combined with (neo)adjuvant chemotherapy offers the best chances for long-term survival for patients with resectable localized pancreatic ductal adenocarcinoma (PDAC). However, even after radical resection, almost all patients will experience local and/or distant disease recurrence after sufficient follow-up, mostly within 2 years. There is a lack of evidence based effective therapeutic options for the significant group of patients with local recurrence only, in terms of improved survival and/or quality of life. In the case of metastatic disease effective chemotherapy has shown to improve survival, but with a median gain survival of 3-4 months. Taken together, this had led to a hesitant attitude towards postoperative recurrence-focused follow-up. Therefore, in most European countries, including the Netherlands, a standardized approach to follow-up after surgery for PDAC is lacking. Furthermore, current PDAC guidelines regarding follow-up are based on expert opinion and other low-level evidence. However, the emergence of more potent local and more effective systemic treatments for PDAC has led to a rising interest in early diagnosis of PDAC recurrence. To detect PDAC recurrence at an early stage and identify patients with good performance status who are most likely to benefit from additional (experimental) treatment, a standardized approach to follow-up with routine imaging and serial serum tumor marker testing is needed. To determine whether early detection of recurrence can lead to improved survival and quality of life, further studies are warranted. Objective: The main objective is to evaluate the impact of a standardized surveillance, with serial tumor marker testing and routine imaging, on overall survival and quality of life in patients with primary resected PDAC, compared to current non-standardized practice. Study design: A randomized controlled trial, nested within an existing prospective cohort (Dutch Pancreatic Cancer Project; PACAP) according to the 'trials within cohorts' (TwiCs) design. Study population: PACAP-participants with histologically confirmed radical resection (R0-R1) of PDAC, who provided informed consent for being randomized in future studies. Interventions: Standardized surveillance, existing of clinical evaluation, serum cancer antigen (CA) 19-9 testing, and contrast-enhanced computed tomography (CT-) imaging of chest and abdomen every 3 months during the first 2 years after surgery. Comparison: Non-standardized clinical follow-up. Endpoints: The main study endpoint is overall survival. The most important secondary endpoint is quality of life. Other secondary endpoints are clinical and radiological patterns of PDAC recurrence, the compliance of patients to our standardized follow-up strategy, the impact of a standardized surveillance on (eligibility for) additional treatment, and the tolerance of additional treatment.

Official Title
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Recurrent Disease Detection After Resection of Pancreatic Adenocarcinoma Using a Standardized Surveillance Strategy: a Nationwide Randomized Controlled Trial

Conditions
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Resectable Pancreatic Ductal Adenocarcinoma, Recurrent Pancreatic Ductal Adenocarcinoma

Intervention / Treatment
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* Other: Standardized surveillance


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Participation in the PACAP cohort with written informed consent for being randomized in future studies Histologically confirmed macroscopically radical resected (R0-R1) pancreatic adenocarcinoma Minimum age of 18 years Exclusion Criteria: Exclusion criteria for contrast-enhanced CT-scan, following the protocol of the department of radiology in each DPCG-affiliated hospital Mentally or physically incapable of consent Participation in other studies with a study-specific follow-up

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Trials within Cohorts (TwiCs)
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Standardized surveillance<br>Standardized surveillance strategy with routine imaging and serum tumor marker testing. | Other: Standardized surveillance<br>* Standardized 3-monthly surveillance with routine imaging and serum tumor marker testing.<br>|
| No Intervention: Non-standardized surveillance<br>Non-standardized surveillance strategy according to current clinical practice. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | The interval between the date of PDAC resection and either death from any cause or last follow-up. | From date of PDAC resection until date of death from any cause or date of last follow-up, whichever came first, assessed up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patient reported Quality of Life as assessed using Exocrine Pancreatic Insufficiency (EPI) questionnaire | Part of the Patient Reported Outcome Measures (PROMs) that are being standardly measured in PACAP-participants. | At baseline and at 3, 6, 9, 12, 18 and 24 months and every subsequent year after enrollment in the PACAP-cohort. Assessed through study completion, up to 24 months | 
| Patient reported non-disease specific health-related Quality of Life (HRQoL) as assessed using the EQ-5D-5L | Part of the Patient Reported Outcome Measures (PROMs) that are being standardly measured in PACAP-participants. | At baseline and at 3, 6, 9, 12, 18 and 24 months and every subsequent year after enrollment in the PACAP-cohort. Assessed through study completion, up to 24 months | 
| Patient reported cancer-specific HRQoL as assessed using the EORTC QLQ-C30 | Part of the Patient Reported Outcome Measures (PROMs) that are being standardly measured in PACAP-participants. | At baseline and at 3, 6, 9, 12, 18 and 24 months and every subsequent year after enrollment in the PACAP-cohort. Assessed through study completion, up to 24 months | 
| Patient reported tumor-specific HRQoL as assessed using the EORTC LQPAN26 | Part of the Patient Reported Outcome Measures (PROMs) that are being standardly measured in PACAP-participants. | At baseline and at 3, 6, 9, 12, 18 and 24 months and every subsequent year after enrollment in the PACAP-cohort. Assessed through study completion, up to 24 months | 
| Patient reported chemotherapy-induced peripheral neuropathy as assessed using the EORTC QLQ-CIPN20 | Part of the Patient Reported Outcome Measures (PROMs) that are being standardly measured in PACAP-participants. | At baseline and at 3, 6, 9, 12, 18 and 24 months and every subsequent year after enrollment in the PACAP-cohort. Assessed through study completion, up to 24 months | 
| Patient reported Quality of Life as assessed using the happiness, hospital, anxiety and depression scale (HADS) | Part of the Patient Reported Outcome Measures (PROMs) that are being standardly measured in PACAP-participants. | At baseline and at 3, 6, 9, 12, 18 and 24 months and every subsequent year after enrollment in the PACAP-cohort. Assessed through study completion, up to 24 months | 
| Patient reported Quality of Life as assessed using the worry of progression of cancer scale (WOPS) | Part of the Patient Reported Outcome Measures (PROMs) that are being standardly measured in PACAP-participants. | At baseline and at 3, 6, 9, 12, 18 and 24 months and every subsequent year after enrollment in the PACAP-cohort. Assessed through study completion, up to 24 months | 
| Compliance of the standardized surveillance strategy | The percentage of patients that either accepts or refuses participation in the intervention-arm, i.e. is willing to undergo a standardized follow-up regime. | Through completion of patient inclusion, an average of 1.5 years | 
| Recurrence-free interval | The interval between the date of PDAC resection and the date of first radiological signs of recurrence, or last follow-up if recurrence is not observed. | From date of PDAC resection until date of first radiological signs of recurrence, or last follow-up if recurrence is not observed, whichever came first, assessed up to 24 months | 
| Prognostic patient specific characteristics and tumor related factors for disease recurrence |  | From date of randomization until disease recurrence or last follow-up, assessed up to 24 months | 
| Role of serum tumor marker testing in detecting recurrent PDAC assessed by the calculated diagnostic accuracy values |  | From date of randomization until disease recurrence or last follow-up, assessed up to 24 months | 
| Eligibility for additional (experimental) treatment at the time of recurrence diagnosis based on the ECOG or Karnofsky performance state, or inclusion criteria for study-related treatment of recurrence |  | At the time of recurrence diagnosis. Assessed through the study, up to 24 months | 
| Reasons to refrain from treatment for recurrence | e.g. poor condition, patients wish, deteriorated condition, progressive disease, advise treating clinician, death, wait-and-see, age. | At the time the patient is assessed eligible for additional treatment. Assessed through the study, up to 24 months | 
| Patients' tolerance of additional treatment for PDAC recurrence as assessed by incidence of adverse events (graded according to NCI CTCAE Version 5.0) |  | Through study completion, an average of 2 years | 
| Morbidity associated with diagnostic testing assessed by the side-effects of diagnostic testing (i.e. fear of disease recurrence) |  | From date of randomization until disease recurrence or last follow-up, whichever came first, assessed up to 24 months | 
| Overall costs of a standardized surveillance strategy versus the costs as incurred with the current non-standardized follow-up assessed according to the EQ-5D questionnaire as part of the PACAP-project, and calculated using to a Markov model |  | After study completion (estimated duration of 3.5 years) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Standardized Surveillance, Follow-up, CA 19-9, Computed Tomography Scan