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

Abstract

Nationwide comprehensive gastro-intestinal cancer cohorts: the 3P initiative

Background: The increasing sub-classification of cancer patients due to more detailed molecular classification of tumors, and limitations of current trial designs, require innovative research designs. We present the design, governance and current standing of three comprehensive nationwide cohorts including pancreatic, esophageal/gastric, and colorectal cancer patients (NCT02070146). Multidisciplinary collection of clinical data, tumor tissue, blood samples, and patient-reported outcome (PRO) measures with a nationwide coverage, provides the infrastructure for future and novel trial designs and facilitates research to improve outcomes of gastrointestinal cancer patients.

Material and methods: All patients aged 18 years with pancreatic, esophageal/gastric or colorectal cancer are eligible. Patients provide informed consent for: (1) reuse of clinical data; (2) biobanking of primary tumor tissue; (3) collection of blood samples; (4) to be informed about relevant newly identified genomic aberrations; (5) collection of longitudinal PROs; and (6) to receive information on new interventional studies and possible participation in cohort multiple randomized controlled trials (cmRCT) in the future.

Results: In 2015, clinical data of 21,758 newly diagnosed patients were collected in the Netherlands Cancer Registry. Additional clinical data on the surgical procedures were registered in surgical audits for 13,845 patients. Within the first two years, tumor tissue and blood samples were obtained from 1507 patients; during this period, 1180 patients were included in the PRO registry. Response rate for PROs was 90%. The consent rate to receive information on new interventional studies and possible participation in cmRCTs in the future was >85%. The number of hospitals participating in the cohorts is steadily increasing.

Conclusion: A comprehensive nationwide multidisciplinary gastrointestinal cancer cohort is feasible and surpasses the limitations of classical study designs. With this initiative, novel and innovative studies

can be performed in an efficient, safe, and comprehensive setting.

The impact of postoperative complications on health-related quality of life in older patients with rectal cancer; a prospective cohort study

Objectives: As result of the aging population and increasing rectal cancer incidence, more older patients undergo treatment for rectal cancer. This study compares treatment course, postoperative complications, and quality of life (QOL) between older and younger patientswith rectal cancer and evaluates the impact of postoperative complications on QOL in the elderly.

Materials and Methods: Patients with rectal cancer participating in a prospective colorectal cancer cohort and referred for radiotherapy between 2013 and 2016 were included. QOL was assessed with the cancer questionnaire of the European Organisation for Research and Treatment of Cancer (EORTC QLQ-C30) before treatment and at three, six, and twelve months. Outcomes were compared between older patients (≥70 years) and younger patients (b70 years) and stratified by presence of postoperative complications.

Results: In total, 115 (33%) older patients and 230 (67%) younger patients were included. Compared to younger patients, older patients underwent significantly more often short-course radiation with delayed surgery (6.1% and 19.1% respectively) and less often chemoradiation (62.6% and 39.1% respectively), and were more likely to undergo a Hartmann procedure with permanent stoma (3.5% and 13.0% respectively) instead of sphincter-sparing surgery (43.9% and 29.6% respectively). Postoperative complication rates were similar (38.5% in older patients versus 34.7% in younger patients). Older patients had worse physical functioning at six and twelve months after diagnosis compared to younger patients. Presence of postoperative complications had a significant stronger impact on physical- and role functioning in older patients.

Conclusion: Older patients undergo more often a tailored treatment approach for rectal cancer than younger patients.With this tailored approach, similar postoperative complication rates and QOL are achieved. However, postoperative complications have a larger negative impact on physical- and role functioning in older patients

which indicates a need for better prediction of postoperative complications in the elderly.

Effect of Neoadjuvant Therapy and Rectal Surgery on Health-related Quality of Life in Patients With Rectal Cancer During the First 2 Years After Diagnosis

The present study describes the trends in quality of life (QOL) of 272 rectal cancer patients treated with neoadjuvant therapy and surgery £ 2 years after diagnosis. During and shortly after treatment, QOL declined substantially and recovered toward pretreatment levels thereafter. However, the functioning scores remained lower compared with the Dutch general population, with postoperative treatment-related symptoms frequently reported.

Introduction: Rectal cancer surgery with neoadjuvant therapy is associated with substantial morbidity. The present study describes the course of quality of life (QOL) in rectal cancer patients in the first 2 years after the start of treatment. Patients and Methods: We performed a prospective study within a colorectal cancer cohort including rectal cancer patients who were referred for neoadjuvant chemoradiation or short-course radiotherapy and underwent rectal surgery. QOL was assessed using the European Organization for Research and Treatment of Cancer core questionnaire (EORTC QLQ-C30) and colorectal cancer questionnaire (EORTC QLQ-CR29) before treatment and after 3, 6, 12, 18, and 24 months. The outcomes were compared with the QOL scores from the Dutch general population and stratified by low anterior resection and abdominoperineal resection. Postoperative bowel dysfunction after low anterior resection was measured using the low anterior resection syndrome score.

Results: Of the 324 patients, 272 (84%) responded to at least 2 questionnaires and were included in the present study. Compared with pretreatment levels, the strongest decline was observed in physical, role, and social functioning at 3 and 6 months after the start of treatment. Global health and cognitive functioning declined to a lesser extend, and emotional functioning gradually improved over the time. Within 24 months, the QOL scores had recovered toward the pretreatment levels in most patients. Compared with the general population, physical, role, social, and cognitive functioning and symptoms of fatigue and insomnia remained significantly worse in patients on longer-term. After low anterior resection, major bowel dysfunction was reported by 44% to 60% of the patients. Increasing urinary incontinence and severe complaints of impotence were observed in patients who had undergone abdominoperineal resection.

Conclusion: Rectal cancer treatment is associated with a significant decline in QOL during the first 6 months after the diagnosis. Within 2 years, most patients return toward pretreatment functioning but could still experience poorer functioning and treatment-related symptoms compared with the general population. These findings support shared decision-making and emphasize the need for postoperative supportive care and novel treatment approaches.

Preferences to receive unsolicited findings of germline genome sequencing in a large population of patients with cancer

Development of a Self-Reported Version of the G8 Screening Tool

Introduction: The G8 is a widely used frailty screening tool in patients with cancer that was designed to be completed by healthcare professionals. A patient-reported version would enable a broader application. Aim of this study was to develop a self-reported version of the G8 and to assess its agreement with the original G8.

Materials and methods: A self-reported version of the G8 was developed with the aid of communication specialists. Patients aged ≥ 70 years from two different study populations were included: 1. Patients with cancer and 2. Patients visiting the geriatric outpatient clinic. The original G8 was completed by an oncology nurse or clinical research assistant and patients completed the self-reported G8. Patients were blinded to results of the original G8. Kappas were calculated to measure the agreement between the self-reported and original G8 for both the individual items as well as for the cut-off for potential frailty (≤14).

Results: 161 patients participated, of whom 104 had cancer (65%). Patients with cancer more frequently completed all items than geriatric patients (all items completed in 94% versus 72%, p < 0.001). The agreement for potential frailty was substantial for patients with cancer (Kappa 0.63) and poor for geriatric patients (Kappa 0.05).

Conclusion: Completion of the self-reported G8 is feasible and agreement of its outcome with the original G8 outcome is sufficient for patients with cancer but not for geriatric patients. The self-reported G8 may therefore be a useful alternative to the original G8 in older patients with cancer.

Performance of Four Platforms for KRAS Mutation Detection in Plasma Cell-Free DNA: ddPCR, Idylla, COBAS z480 and BEAMing

Multiple platforms are commercially available for the detection of circulating cell-free tumour DNA (ctDNA) from liquid biopsies. Since platforms have different input and output variables, deciding what platform to use for a given clinical or research question can be daunting. This study aimed to provide insight in platform selection criteria by comparing four commercial platforms that detect KRAS ctDNA hotspot mutations: Bio-Rad droplet digital PCR (ddPCR), BioCartis Idylla, Roche COBAS z480 and Sysmex BEAMing. Platform sensitivities were determined using plasma samples from metastatic colorectal cancer (mCRC) patients and synthetic reference samples, thereby eliminating variability in amount of plasma analysed and ctDNA isolation methods. The prevalence of KRAS nucleotide alterations was set against platform-specific breadth of target. Platform comparisons revealed that ddPCR and BEAMing detect more KRAS mutations amongst mCRC patients than Idylla and COBAS z480. Maximum sample throughput was highest for ddPCR and COBAS z480. Total annual costs were highest for BEAMing and lowest for Idylla and ddPCR. In conclusion, when selecting a platform for detection of ctDNA hotspot mutations the desired test sensitivity, breadth of target, maximum sample throughput, and total annual costs are critical factors that should be taken into consideration. Based on the results of this study, laboratories will be able to select the optimal platform for their needs.