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

Figures & data

Table 1. Clinical data collection within the prospective Dutch colorectal cancer cohort.

PART A: Patient ID and data sources	PART B: Pretreatment record	PART C: Treatment record	PART D: Post-treatment/follow-up record
Patient identification & demographics	Medical history	Radiotherapy*	Oncological follow-up
– Patient-ID code	Cancer specific	Setting (neo-adjuvant/adjuvant)	Recurrence*
– Birth information (date and city)	– Date, location, type, treatment, treatment outcome	Indication for radiotherapy	– Recurrence [date, number, location(s)]
– Gender	Comorbidity	Treatment	– Treatment of recurrence (new PART C entry)
	– Cardiac, pulmonal, vascular, gastro-intestinal	– Start date first fraction	– Setting (curative/palliative)
	– Neurological, gynecological, urological	– Standard: # fractions, fraction dose, total dose	Metastases*
Data source	– Muscle/bones, endocrine	– Boost: # fractions, fraction dose, total boost dose	– Metachronic metastases [date, number, location(s)]
– Hospital		– Total received dose and fractions	– Treatment of metastases (new PART C entry)
– Patient number within hospital	Intoxication	– Stop/completion date	– Setting (curative/palliative)
Data capture	– Smoking at diagnosis	– Response (TRG, ycTNM)
– ID of person who captures data	– Alcohol use at diagnosis	– Adverse events (date, cause, management)	Complications*
			– Grade 3/4 adverse events or complications
Study participation within the cohort	Physical examination	Medical oncology*
– Number and name of studies/trials	– BMI (length & weight)	Setting (neo-adjuvant/adjuvant)	Survival
– Date(s) of inclusion	– WHO performance status	Indication for systemic therapy	– Date of last hospital visit
– Date(s) of completed study/trial follow-up		Treatment	– Death (including date and cause)
	Diagnosis & tumor information	– Start date first cycle
	– Sequential tumor number	– Agent, dose, number of cycles
	– Date of diagnosis	– Total received dose and cycles	* Multiple entries are allowed within each tumor episode
	– Source/procedure of diagnosis	– Stop/completion date
		– Response (TRG, ycTNM)
	Laboratory investigations	– Adverse events (date, cause, management)
	– CEA
		Surgery*
	Diagnostic work-up	ASA classification
	Endoscopy	Procedure
	– Date, hospital, procedure, procedure complete?	– Date, hospital
	– Number of tumors/polyps, distance from anal verge	– Setting (elective/acute)
	– Endoscopic treatment	– Approach (open/laparoscopic/robot)
	Pathology	– Type [(Sub)Total Colectomy, LAR, APR, Hartmann]
	– Type, differentiation, T-stage	– Anastomosis (type, stapled/sewn)
	Imaging	– Date of discharge
	– Modalities, date(s), hospital	Stoma
	– cTNM, MRF involvement, distance from anal verge	– Date, hospital
		– Setting (elective/acute)
	Multidisciplinary Tumor Board – Date & final staging	– Temporary/definitive
		– Type (ileostoma, colostoma)
		– Date of stoma reversal – Peri-operative complications (anastomic leakage, abscess, ileus) – Post-operative complications (incl. wound complications)
		Pathology*
		– pTNM
		– Tumor regression grade
		– Radicality of resection
		– Circumferential resection margin (CRM)
		– # lymph nodes & # positive lymph nodes in  specimen
		– Angio– and lymphatic invasion
		– Perforation of the bowel
		– Molecular markers (BRAF, RAS, MSI status)

Table 2. Ongoing studies embedded in the PLCRC cohort currently recruiting patients.

Name study	Design	Description of study	Study population	Sample size (n)
Rectal Boost	RCT*	Effect of a pre-operative dose-escalation BOOST versus standard chemoradiation on pathologic response rates in locally advanced rectal cancer [42]	T3 with threatened mesorectal fascia (<1 mm), T4 or N2M0 rectal cancer	60 vs. 60
Sponge	RCT*	Effect of a retractor SPONGE during laparoscopic rectal cancer surgery versus Trendelenburg positioning on peri-operative complications and hospital stay [44]	Stage I-IV CRC undergoinglaparoscopic surgery	94 vs. 94
PROTECT	Prospective cohort	PlcRc cOhorT: diEtary intake after diagnosis and ColorecTal cancer outcomes	Stage I-IV CRC	1000
CONNECTION	Validation study with different work packages including a prospective cohort study	A nationwide COloN CaNcer rEgistry and stratifiCaTION effort for the development and validation of genetic, proteomic and histopathological assays to stratify patients for adjuvant therapy	Stage II-III colon cancer	NA
MEDOCC	Prospective cohort	Molecular Early Detection of Colorectal Cancer study to investigate the prognostic value of circulating tumor DNA [45]	Stage II colon cancer	846
SPECTRE	Pilot study	Ultra-high field 7.0 Tesla MR SPECTRoscopy to monitor capEcitabine metabolism in liver metastases	metastatic CRC	26
Recap	Case-control	Case match control study investigating the benefit of last line regorafenib treatment	Metastatic colon cancer and metastatic RAS wildtyperectal cancer	125 vs. 125
Quality of life study 1	Prospective cohort	Impact of short-course radiation versus long-course chemoradiation for rectal cancer on quality of life	Stage II-IV rectal cancer	>60 vs. >60
Quality of life study 2	Prospective cohort	Quality of life comparison between patients undergoing radiation followed by low anterior resection versus abdomino-perineal excision	Stage II-IV rectal cancer	>100 vs. >100

* Randomized controlled trial according to the cohort multiple randomized trial design (Box 2).

Box 1. the main objectives of the Prospective Dutch ColoRectal Cancer cohort (PLCRC) are:

To execute a prospective observational cohort study aiming to include all Dutch CRC patients and follow them until death. To prospectively collect high quality data on medical history, comorbidities, clinical characteristics, imaging, pathology results, tumor characteristics, treatment, survival, recurrence, hospitalization, adverse events, toxicity and (long-term) outcomes of experimental interventions (Table 1). To collect, store and make available blood and tumor tissue samples. To systematically collect patient-reported outcomes on quality of life, workability and functional outcomes. To provide detailed data on daily clinical care in the Netherlands. To create an infrastructure to facilitate studies of different nature, including: Prognostic and predictive research; Biological research and (epi-)genetic research; Studies that compare novel therapies or interventions in a target population according to the innovative cohort multiple randomized controlled trial (cmRCT) design serving as a pragmatic alternative for classic RCTs; Cost-effectiveness studies.

Box 2. The cohort multiple randomized controlled trial design.

The basis of the cohort multiple randomized controlled trial (cmRCT) design is a prospective observational cohort of patients with a certain condition [20], in our case CRC, in which all patients in principle undergo standard care. Within this cohort, clinical characteristics and standardized outcome measures are collected at baseline and regularly during follow-up. Clinical and self-reported data are used to compare effectiveness and safety of trialed interventions.

Practically, when an RCT is conducted within the cmRCT cohort, the first step is to identify a subcohort of all patients eligible for the intervention. Some of these patients are randomly selected and offered the experimental intervention (intervention group). If patients accept the offer, they are sure to undergo the experimental intervention. If they refuse they will undergo standard care. Eligible patients in the subcohort not randomly selected (control group), undergo standard treatment and do not receive any information on the trial. Outcomes are compared between randomly selected and non-selected patients. This process can be repeated for multiple (experimental) interventions simultaneously, offering (more) reliable direct comparisons between interventions and standard care.

In the cmRCT design a patient-centered informed consent procedure is obtained [42] by asking all patients to give ‘broad consent for randomization’ after enrollment [42,43]. This allows researchers to randomly selected patients from the cohort, and offer them experimental interventions, while patients who are not randomly selected serve as controls and undergo standard care without further notification. When informing patients about broad consent for randomization, we explicitly state that not all patients that consent will be offered an experimental intervention as offers are based on random selection. When they got offered an experimental intervention they can either accept the intervention or they can refuse and undergo standard care. Also, they are told that they may become (temporarily) ineligible for future trials if they already participate in a trial which measures interfering endpoints. We ensure that patients will never be withheld proven effective care.

With this consent procedure we aim to mimic clinical practice, where people are usually not told about treatments they will not/cannot receive. The patient-centered informed consent is expected to prevent cross-over and disappointment bias, especially in situations where, regardless of clinical equipoise, a new intervention is highly preferred by doctors and patients. Asking broad consent for randomization also deals with the controversial ethical aspect of pre-randomization (as introduced by Zelen [44]) by obtaining upfront consent from all patients for randomization and data use in future comparative research, thereby not randomizing patients without prior notification and their consent.

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