Study retention and attrition in a longitudinal cohort study including patient-reported outcomes, fieldwork and biobank samples: results of the Netherlands quality of life and Biomedical cohort study (NET-QUBIC) among 739 head and neck cancer patients and 262 informal caregivers

Longitudinal observational cohort studies in (cancer) patients are important to move research and clinical practice forward. However, study retention (continued study participation) can be compromised in such studies. Attrition (drop-out) limits the statistical power of research and, in case attrition is selective, may lead to biased results and hamper representativeness of study findings [1]. Especially in studies among cancer patients study attrition may occur due to factors such as mortality and long-term side-effects of treatment.

Previous longitudinal cohort studies provided insight into study retention and attrition among cancer patients [2‐9]. Two small studies in which patients were asked to complete patient-reported outcome measures (PROMs) showed retention rates of 15% among 47 adolescent and young cancer patients (1–1.5 year follow-up) and 96% among 121 breast cancer patients (1 year follow-up) [2, 3]. In addition, Ness et al. (2016) [9] presented results of the Head and Neck 5000 study and showed that among 5356 head and neck cancer (HNC) patients 75% completed PROMs, and of 90%, 85% and 42% respectively oral rinse samples, blood samples and paraffin embedded tumor blocks were collected at baseline. At 4- and 12-months follow-up 63 and 57% of the patients completed the PROMs. In addition, Perez-Cruz et al. (2018) [6] reported that 67% of 744 advanced cancer patients showed up for a follow-up research visit at 2–5 weeks follow-up. Leuteritz et al. (2018) [5] showed that 89% of 577 young adult cancer patients completed PROMs at 1 year follow-up. A study by Ramsey et al. [7] with yearly PROM collection among 2625 colorectal cancer patients showed a retention rate of 58% of those alive (56% of all patients) at 2-years follow-up and 51% (47% of all patients) at 4 years follow-up. A study by Spiers et al. (2018) [8] among 1227 prostate cancer patients who were invited to complete PROMs at 3–6 years follow-up showed that 69% of those alive (62% of all patients) participated. Finally, Fossa et al. (2020) [4] showed that among 1436 testicular cancer patients 64% of those alive (54% of all patients) completed all three PROMs assessments over a time period of 17 years. In these studies retention rates were higher among patients who were younger [4, 7, 8], who were higher-educated [7, 8], had a higher socio-economic status [4, 7, 8], and had better clinical [4, 6, 8] and patient-reported outcomes [6, 7]. Mixed results were reported regarding gender [5‐7].

Except for the study of Perez-Cruz et al. (2018) [6] and Ness et al. (2016) [9], all previous studies focused on the collection of a limited set of PROMs every 1 to 6 years. No study investigated retention and attrition in a longitudinal observational cohort study comprising different types of data, such as collection of PROMs, conduction of fieldwork assessments and collection of biobank samples, with multiple measurements per year. Also, so far, only in one study retention rates among informal caregivers of cancer patients was investigated [10]. This study of Fernix et al. (2006) [10] showed that among 206 informal caregivers of terminally ill cancer patients (all types) 85% participated in a face to face interview at 13-months follow-up.

Therefore, the aim of this study was to investigate study retention and attrition in a longitudinal cohort study with a comprehensive assessment protocol among HNC patients and their informal caregivers using data of the Netherlands Quality of Life and Biomedical Cohort Study (NET-QUBIC), and to explore sociodemographic and clinical factors associated with study retention. NET-QUBIC is a longitudinal observational cohort study among 739 HNC patients and 262 informal caregivers with collection of PROMs, fieldwork data (interview, objective tests and medical examination) and biobank materials from before start of treatment up to 2-years follow-up [11, 12]. In a previous study patients evaluated this comprehensive assessment protocol as feasible in terms of time investment and intimacy [11]. The overarching objective of NET-QUBIC is to optimize diagnosis, treatment and supportive care by advancing interdisciplinary research [11, 12]. So far, more than 20 derivate studies are ongoing or have been published that use NET-QUBIC data and samples [12‐18]. Further insight in study retention and attrition will facilitate interpretation of findings derived from these studies. Also, this study contributes to designing future longitudinal cohort studies with comprehensive assessment protocols among cancer patients.

In this study data of the NET-QUBIC observational cohort study was used [12]. Recruitment of NET-QUBIC participants took place in 7 HNC centers throughout the Netherlands. In total, 739 newly diagnosed HNC patients and 262 caregivers were recruited (March 2014 to June 2018). Inclusion criteria were previously untreated patients with newly diagnosed HNC (oral cavity, oropharynx, hypopharynx, larynx, unknown primary; all stages); age ≥ 18 years; treatment with curative intent; able to write, read, and speak Dutch. Patients were excluded in case they were diagnosed with lymphoma, skin malignancies or thyroid cancer; were unable to understand the questions or test instructions; did not provide informed consent or had severe psychiatric co-morbidities (schizophrenia, Korsakoff’s syndrome, severe dementia). A partner, family member or close friend of the patient was asked to participate as informal caregiver. The study protocol was approved by the Institutional Review Board at VUmc (2013.301(A2018.307)-NL45051.029.13) and at all local participating centers. The biobank protocol was also approved by the biobank committee of VUmc (2018.406). All patients and caregivers signed informed consent.

Previously it was shown that among 1861 patients invited for NET-QUBIC 739 patients participated (40%) [12]. In addition, 262 informal caregivers participated. Table 1 provides insight into the baseline characteristics of all patients and informal caregivers.

The aim of this study was to investigate study retention and attrition, and sociodemographic and clinical factors associated with study retention up to two years follow-up in a longitudinal cohort study among HNC patients and their informal caregivers. At 2-years follow-up, study retention was 80% among patients alive at that time-point (66% among all included HNC patients) and 70% among informal caregivers with a patient still actively participating in the study (52% among all included informal caregivers). Reasons for study attrition among HNC patients were mostly mortality-related, followed by logistic, physical, or psychological factors. Both sociodemographic and clinical outcomes influenced participation in the different NET-QUBIC (sub) components (PROMs, tumour biopsy, blood, and saliva) at baseline. Study retention in general (participation in at least one NET-QUBIC component) at 2-years follow-up was associated with a better physical performance and lower comorbidity score (patients still alive) and younger age (caregivers).

The NET-QUBIC retention rate of 66–80% among HNC patients is relatively high compared to the retention rate over time of 56% (among all patients included at baseline) to 58% (among all patients included at baseline and believed to be alive) at 2-years follow-up found in a previous observational cohort study among colorectal cancer patients (recalculated) [7]. It is also high in comparison to another large observational cohort study (i.e. Head and Neck 5000) which showed that 57% of HNC patients completed PROMs at 1-years follow-up [9]. A possible explanation might be that, by study design, we facilitated study retention by performing the fieldwork assessment at the patients’ home (and the possibility of a fieldwork assessment at the hospital when preferred by the patient), by sending reminders by post in collecting PROMs data, and by sending yearly newsletters to patients and informal caregivers. A previous meta-analysis on the effectiveness of retention strategies in both clinical and non-clinical observational cohort studies also showed that offering site and home visits might improve study retention. However, no effects of newsletters and reminders were found [1]. The high retention rate in the NET-QUBIC study might also result from the design of the NET-QUBIC study, in which patients were allowed to participate in a subset of NET-QUBIC components (e.g., fieldwork and biobank component only) to minimize study attrition. When we focus on the collection of PROMs, 67% of patients alive participated at 2-years follow-up, whereas 67% of patients alive participated in the fieldwork component and 73% in the biobank component. These high percentages per NET-QUBIC component support the previous findings of van Nieuwenhuizen et al. [11], who showed that a comprehensive assessment protocol as used in the NET-QUBIC study is evaluated as feasible by patients in terms of time investment and intimacy. The NET-QUBIC retention rate of 61 and 52% (all informal caregivers) to 75 and 70% (all informal caregivers with a patient still actively participating in the study) at respectively 1 and 2-years follow-up is lower than the retention rate of 85% at 13-months follow-up reported in a study in which face to face interviews were conducted among informal caregivers of terminally ill patients [10]. An explanation for this difference might be that informal caregivers are more likely to participate in face to face interviews in comparison to completing PROMs (in NET-QUBIC informal caregivers only filled in PROMs at the follow-up time points), but more research is needed on this hypothesis.

The most important reason for study attrition among HNC patients in the NET-QUBIC study was mortality, followed by logistic, physical or psychological reasons, which are also common reasons for study attrition in clinical trials among cancer patients [19, 20]. In contrast to previous findings [4, 7, 8], age was not associated with study retention in general. In line with previous studies [4, 6, 8], however, better clinical outcomes such as a better physical performance and favourable comorbidity score were found to be associated with study retention. Together with previous results of Verdonck-de Leeuw et al. (2019) [12] who showed that HNC patients who participated in the NET-QUBIC study were younger, more often male, diagnosed with oropharyngeal cancer, and treated with radiotherapy and chemotherapy (compared to all HNC patients diagnosed), these findings indicate that NET-QUBIC data and samples might be slightly selective. Also, data and samples of informal caregivers of HNC patients are not entirely representative, as older caregivers were more likely to continue study participation. Future NET-QUBIC researchers should be aware of these differences in participation and retention when writing the data analysis plan of their NET-QUBIC study and reflect on the representativeness of their findings in the discussion section. In addition, future cohort studies might benefit from oversampling specific subgroups such as patients with poor clinical outcomes or younger caregivers.

Besides differences in study retention over time, some minor differences were found between patients who did and who did not participate in the different NET-QUBIC (sub) components at baseline. Patients with worse clinical outcomes (e.g., worse physical performance) were less likely to complete PROMs and to participate in saliva collection. These (sub) components needed to be performed by the patient without the researcher/fieldworker present, which might be more difficult for patients with a poorer physical performance (e.g., due to inability to open saliva tubes or to post the PROMs/saliva tubes). Tumor biopsies, however, were more often collected among patients with worse tumor-specific and clinical outcomes. This might be explained by the NET-QUBIC study design, in which additional tumor biopsies were only collected in case tumor biopsies were already collected for diagnostics purposes and sufficient tumor tissue was available. Finally, older age was associated with higher participation in the collection of saliva samples. Only patients who participated in the fieldwork component were asked to collect saliva samples the following day. The higher age among participants of the saliva component might, consequently, directly result from the higher age among participants of the fieldwork assessment (although non-significant, p-value of 0.06). Our hypothesis is that working-aged patients are less likely to participate in the fieldwork/saliva (sub) component due to work obligations. These differences among participants and non-participants might limit representativeness of NET-QUBIC data and samples. However, it might also improve representativeness of NET-QUBIC data. For example, the older age among patients who participated in the fieldwork or saliva (sub) component may counteract the lower recruitment rate among older HNC patients found by Verdonck-de Leeuw et al. [12].

To improve retention rates in future longitudinal cohort studies in cancer patients and their informal caregiver, we, suggest to personalize the method of participation and offer both online and paper and pencil options to complete the PROMs. In the NET-QUBIC study we asked all patients and informal caregivers to complete the PROMs using paper and pencil, as it was estimated that about 30% quite some HNC patients have no internet or limited computer skills has no access to the internet or limited computer skills [21, 22]. Some, potentially younger, HNC patients and informal caregivers may, however, be more likely to complete PROMs on a computer or smartphone. In addition, although we have no data to support this assumption, we assume that the involvement of a dedicated research nurse or research coordinator for a long period of time is of great importance for study retention.

A strength of this study is that it is the first study that investigated study retention and attrition in a longitudinal cohort study among cancer patients with PROMs, fieldwork and biobank assessments. A limitation of this study is, however, that, due to the design of the study, only sociodemographic and clinical characteristics could be compared among groups of patients and caregivers (and not PROMs). Also, sociodemographic and clinical characteristics of NET-QUBIC participants were only compared for the main NET-QUBIC component (PROMs, fieldwork, biobank) and a selection of NET-QUBIC subcomponents (tumor biopsy, blood, oral rinse and saliva). Due to patient or caregiver-related factors specific PROMs or subcomponents of the fieldwork assessment may, however, be missing and influence representativeness of data (e.g., specific PROM questions on sexuality may be left open by certain groups of patients or informal caregivers).

Retention rates of the NET-QUBIC study are high. Nevertheless selection may have occurred during the study, which might slightly limit representativeness of NET-QUBIC data and samples. To facilitate representativeness of study findings future cohort studies might benefit from oversampling specific subgroups such as patients with poor clinical outcomes or higher comorbidity and younger caregivers.