Prospective Dutch colorectal cancer cohort : an infrastructure for long-term observational , prognostic , predictive and ( randomized ) intervention research

Systematic evaluation and validation of new prognostic and predictive markers, technologies and interventions for colorectal cancer (CRC) is crucial for optimizing patients’ outcomes. With only 5–15% of patients participating in clinical trials, generalizability of results is poor. Moreover, current trials often lack the capacity for post-hoc subgroup analyses. For this purpose, a large observational cohort study, serving as a multiple trial and biobanking facility, was set up by the Dutch Colorectal Cancer Group (DCCG).  The Prospective Dutch ColoRectal Cancer cohort is a prospective multidisciplinary nationwide observational cohort study in the Netherlands (yearly CRC incidence of 15 500). All CRC patients (stage I–IV) are eligible for inclusion, and longitudinal clinical data are registered. Patients give separate consent for the collection of blood and tumor tissue, filling out questionnaires, and broad randomization for studies according to the innovative cohort multiple randomized controlled trial design (cmRCT), serving as an alternative study design for the classic RCT. Objectives of the study include: 1) systematically collected long-term clinical data, patient-reported outcomes and biomaterials from daily CRC practice; and 2) to facilitate future basic, translational and clinical research including interventional and cost-effectiveness studies for both national and international research groups with short inclusion periods, even for studies with stringent inclusion criteria.  Seven months after initiation 650 patients have been enrolled, eight centers participate, 15 centers await IRB approval and nine embedded cohortor cmRCT-designed studies are currently recruiting patients.  This cohort provides a unique multidisciplinary data, biobank, and patient-reported outcomes collection initiative, serving as an infrastructure for various kinds of research aiming to improve treatment outcomes in CRC patients. This comprehensive design may serve as an example for other tumor types. ARTICLE HISTORY Received 6 March 2016 Revised 22 April 2016  May 2016 Worldwide, colorectal cancer (CRC) is the third most common malignancy in men and second in women . With a continuously rising incidence, an estimated 1.35 million new cases are diagnosed yearly, associated with 694 000 annual deaths. In the past decades, substantial progress has been made in diagnosis and treatment of CRC, resulting in an increasing number of CRC survivors [2–8]. The implementation of national CRC screening programs is expected to increase the incidence of CRC . The increasing incidence of CRC, in combination with improved survival rates, has led to high numbers of people living with (the consequences of) CRC. In addition to treatment parameters and outcomes, also quality of life, workability, and daily functioning during and after CRC treatment are becoming increasingly important parameters in research. There is no consensus on the use of prognostic parameters in CRC, and predictive factors for treatment are scarce. Also, there is a growing availability of new molecular markers [10–13] and innovative treatment options. This puts increasing pressure on the current research system, as large CONTACT M. Koopman, m.koopman-6@umcutrecht.nl Department of Medical Oncology, University Medical Center Utrecht, Heidelberglaan 100, 3508 GA Utrecht, The Netherlands *Authors contributed equally Trial registration PLCRC is registered at Clinicaltrials.gov under NCT02070146.  This warranted large number greatly exceeds the amount of patients that currently participate in clinical trials (5–15%) [14–16]. Low recruitment rates may also imply selective inclusion of patients in trials rather than representative population samples , which may result in limited external validity of outcomes. The danger of the extrapolation of study results to the general population was recently shown. Survival outcomes of patients with metastatic CRC (mCRC) treated within the scope of a randomized study were significantly better than the survival outcomes in patients not fulfilling the study eligibility criteria and treated outside the trial with the same drugs during the same period [17,18]. Moreover, study designs classically used for comparative research often lack the ability to provide sufficient data for subgroup treatment effects or post-hoc evaluation. For example, immunotherapy showed to be effective in mCRC patients with microsatellite instability (MSI). As MSI is only observed in 3–5% of the mCRC patients, the conduction of a large randomized phase 3 trial will be challenging [19]. It is therefore desirable to include all these patients in a large representative cohort of CRC patients who are prospectively followed for relevant outcomes that enables to study the value of novel prognostic and predictive biomarkers in large, but also small subgroups of patients. It would be ideal to use data from routine sources, such as hospital systems or (cancer) registries, but these sources often lack the required detail about (changes in) treatments, doses, toxicity, and response, which is paramount for this purpose. As an alternative, a large observational cohort has the advantage that it can provide a standardized data collection, dedicated data monitoring and intensive follow-up, all of which are especially valuable for long-term research in prognostic or predictive determinants. Ideally, all new interventions should be evaluated in randomized controlled trials (RCTs) as this is considered the gold standard to prove effectiveness. However, this design in itself is often not only complicated by slow recruitment rates and limited generalizability , it is also subject to a considerable delay between conceptualization and start, limited long-term follow-up, inadequate collection of patient-reported outcomes (PROMs), high non-completion rates and high costs [16]. An innovative alternative proposed for the classic RCT is the ‘cohort multiple randomized controlled trial’ (cmRCT) [20]. This design was originally developed as an alternative for classic pragmatic RCTs, and combines useful features from both classic RCTs (randomization) and prospective observational cohort studies. The design is characterized by three features: (1) patient-centered informed consent approach; (2) framework to systematically collect long-term clinical followup as well as PROMs; and (3) efficient recruitment for trials by asking patients to give ‘broad consent for randomization’ in future trials. Unique features of the cmRCT design are that it allows multiple randomized trials to be conducted simultaneously and that patients can participate in multiple nonconflicting trials at the same time [20]. The design itself and its implementation in this study are explained in more detail in Box 2. We believe that a prospective observational cohort study can provide a standardized and validated collection of longterm clinical data, tissue and blood samples and PROMs to establish a continuous source for a variety of research purposes. This research database can, among others, be used to investigate what (intrinsic and environmental) factors are associated with survival and PROMs, to find new predictive markers for treatment outcomes and side effects, and to develop more accurate diagnostic tests and efficient followup surveillance strategies.