Insights from using patient-reported outcomes as an intervention during cancer treatment in Denmark: potential reasons for limited effectiveness

Abstract

Background

In this comment, we discuss the differences between four Danish randomized controlled trials (RCTs) exploring the effect of electronic patient-reported outcomes (ePROs) as an intervention during cancer treatment and the seven studies included as the basis for the ESMO clinical practice guideline on ePRO in cancer care. We aim to elucidate possible reasons for the lack of effect in a Danish context, which is relevant if ePRO is to be applied in oncological clinical practice on a larger scale.

Main text

The RCTs underpinning the ESMO guideline demonstrated how the use of ePROs as an intervention improved symptom control, reduced emergency use, hospitalizations, unplanned healthcare episodes, and promoted better physical function. Notably, one study reported an improvement in overall survival. In the Danish studies, the effects were less clear. None of the Danish RCTs investigating ePRO as an intervention during cancer therapy, compared to standard care, showed a significant impact on primary clinical outcomes. We compared the design and performance concerning the number of patients, the questionnaire used for PRO, software, symptom management algorithm, designated staff capacity, primary outcome, and results reported. The Danish studies included fewer patients (138–682) than the ESMO guideline studies (252–1191). A variety of questionnaires and software were used. Six of seven ESMO guideline studies had designated staff to handle the ePROs, whereas three out of four Danish trials lacked this key component.

Conclusion

We believe that one possible explanation for the lack of effect in the Danish RCTs can be explained by the absence of designated staff capacity to handle ePROs. It is important to take such matters into account before the large-scale application of PRO in health care practice if the effect of PROs in clinical practice is to be achieved.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12955-025-02417-4.

Background

Finding the best ways to utilize electronic patient-reported outcomes (ePROs) during cancer treatment remains challenging for various reasons, such as challenges in electronic health integration, clear guidelines for responding to specific ePRO-data, provider overload, resource constraints, and engagement and adherence from both patients and clinicians as well as health care leadership support. However, ePROs seem to be important tools for improving cancer trajectories in a health care system aiming to deliver quality cancer clinical care [1].

Already in 2004, Velikova et al. suggested, in an RCT, that the completion of PROs in itself might affect patients´ well-being. The study further showed that when patient responses were discussed with clinicians, it significantly increased the attention given to chronic symptoms and enhanced overall well-being [2]. Since then, PROs have increasingly become a part of cancer care projects with their use transitioning from paper-based methods to electronic formats due to their efficiency, real-time data capture, reduced errors, and ease of integration into healthcare systems [3]. ePROs can provide insights into a patient’s quality of life, symptoms, and emotional well-being in real-time, complementing clinical assessments and helping to understand the full impact of cancer and its treatment. Additionally, regular monitoring using PROs may facilitate the early identification and management of symptoms or side effects, potentially leading to timely management [3].

Thus, ePROs are utilized in clinical oncology trials and practice to enhance clinical decision-making and shape healthcare policy. In a recent editorial, Bellino et al. highlight the central and important role of PROs in oncology trials by providing data on tolerability and effectiveness. Furthermore, they emphasize that PROs are invaluable in clinical practice, providing direct insights into patients’ perspectives to help align care with patients’ needs and priorities [4]. This is supported by a recently published study involving 33 cancer sites in two European countries, which demonstrated that it is feasible to implement weekly ePROs in routine care and that the patients experienced a significant improvement in symptom burden [5]. Notably, one key factor to this success may be that healthcare organizations utilizing remote patient monitoring received reimbursement from the French government for the symptom management coordination [5]. Another study on the patient-perceived benefits and limitations of remote symptom monitoring found that PROs enhanced proactive symptom monitoring and improved the patient-clinician relationship during cancer treatment [6].

To address the growing recognition of the importance of ePROs in improving cancer care, the European Society for Medical Oncology (ESMO) has developed a guideline in 2022 to standardize, enhance, and promote their effective use across clinical practice, research, and policy. Overall, the ESMO Clinical Practice Guideline for PROs advocates for incorporating PROs as a fundamental component of cancer care and research during all the phases of the cancer trajectory: from the onset of diagnosis and treatment, during active treatment, in survivorship and follow-up care, and palliation at the final stages of life [7].

The ESMO Guideline is based on seven ePRO studies from various European countries and the United States. The studies demonstrate the positive impacts of PROs as interventions in randomized controlled trials (RCTs), though with differing outcomes [7]. Given the less clear effects of the use of ePROs in our own experience in Denmark, we decided to compare Danish RCTs examining the effects of ePRO interventions during cancer treatment with studies included in the ESMO guidelines on ePROs in cancer care. We aimed to explore potential reasons for the lack of effect observed in the Danish context, offering insights into how PROs can be more effectively integrated into oncological practice.

The use of ePROs during active cancer treatment

When it comes to the period during which the patients undergo active treatment for their cancer disease, monitoring of side effects and symptoms is of particular interest, which is also the focus of this comment. The RCTs underpinning the ESMO guideline demonstrated how the use of ePROs as an intervention improved symptom control [8–13], reduced emergency use [12], hospitalizations [14], unplanned health care episodes [11], and promoted better physical function [13]. Notably, one study reported an improvement in overall survival [12]. Furthermore, many of the studies also observed a better quality of life among the participants, who were randomized to the ePRO interventions [10–13]. The ESMO studies are listed in Table 1. However, not all study settings have yielded similar positive outcomes when using ePROs as seen in the ESMO guidelines. A 2024 mini-review examined studies utilizing ePROs during active treatment in Denmark [15]. Of the 19 studies identified in the mini-review, four were RCTs [16–19], making them suitable for comparison with the ESMO studies (Table 1). The remaining 15 studies were non-randomized and thus excluded from consideration.

Table 1.

Overview of the RCTs presented in the ESMO clinical practice guideline for PRO and the RCTs presented in the Danish mini-review focusing on pros as the intervention

Author, year (Country)	Journal	Study type	No. of patients	Questionnaire	DIGITAL PLATFORM
ESMO clinical practice guideline for PRO studies
Berry, 2014 [8]  (US)	Journal of Clinical Oncology	RCT	752	SDS-15	ESRA-C
Strasser, 2016 [9]  (CH)	Annals of Oncology	Cluster-randomized	264	ESAS	E-MOSAIC
Basch, 2016 [12]  (USA)	Journal of Clinical Oncology	RCT	766	NCI-CTCAE	STAR
Mir, 2020/2022 [14]  (F)a	Nature Medicine	RCT	609/559	PRO-CTCAE	CAPRI RPMS
Absolom, 2021 [10]  (UK)	Journal of Clinical Oncology	RCT	508	NCI-CTCAE	eRAPID
Mooney, 2021 [11]  (USA)	Journal of Clinical Oncology	RCT	252	MDASI and NIH PROMIS	SCH
Basch, 2021 [13]  (USA)	Journal of Clinical Oncology	Cluster-randomized	1191	PRO-CTCAE	PRO-TECT
Danish PRO studies
Pappot, 2021 [16]  (DK)	Breast Cancer	Cluster-randomized	682	PRO-CTCAE	Ambuflex
Tolstrup, 2020 [17, 20]  (DK)	Journal of Patient-reported Outcomes	RCT	138	PRO-CTCAE	Ambuflex
Taarnhøj, 2023 [18]  (DK)	Journal of Patient-reported Outcomes	RCT	228	PRO-CTCAE	Ambuflex
Friis, 2024 [19]  (DK)	JCO Clinical Practice	RCT	494	EORTC QoL	Ambuflex

^aAbstract (2020) From the ESMO guideline, manuscript published in 2022 [14]

The Danish trials also measured primary outcomes such as improved symptom monitoring, better overall survival, and fewer hospitalizations or emergency visits, but none of the four studies met their primary endpoint. The discrepancy between the promising results in some studies (as highlighted by the ESMO guideline) and the lack of significant effects in the Danish context warrants further investigation. It is essential to understand the underlying reasons for these divergent results, particularly if PROs are to be more widely implemented in oncological clinical practice. Gaining insights into these differences will be crucial for refining PRO applications and ensuring their effectiveness in real-world clinical settings.

Training of patients, advice about self-management actions, and alerts

In the context of implementing ePROs, patient training on how to report symptoms and/or self-administer interventions is a crucial part of ensuring their effectiveness and reliability. This process typically involved teaching patients how to use the digital platforms used in various studies, such as STAR or eRAPID. Such training occurred in five of the ESMO studies [8, 10, 12–14] and in one of the Danish studies [17] (Fig. 1; Table 2). Another key factor in achieving the effectiveness of PROs as an intervention appears to be providing self-management advice to patients, generated from pre-defined algorithms either in a pre-distributed booklet or electronically. Four [8, 10, 11, 13] out of the seven ESMO studies had symptom management algorithms that guided the patients on what to do in case of symptoms (Fig. 1; Table 2), which was only true for one of the Danish studies [18]. In one Danish study, information on self-management was not provided in the publication [16]. In addition, in case of severe symptoms, alerts to the patients were triggered, telling them to call the hospital in five ESMO studies [8, 10–12, 14]. Three out of the four Danish studies had alerts, which prompted the patients to contact the hospital when a pre-defined threshold was exceeded [17–19] (data not shown in Fig. 1).

Fig. 1.

Visual representation of selected elements in the RCTs presented in the ESMO Clinical Practice Guideline for PRO and the RCTs presented in the Danish mini-review focusing on PROs as the intervention. A blue dot means that the element is described in the study

Table 2.

Definition of the elements shown in Fig. 1

Definition of elements
Training of patients	Mentioning training in how to use the digital platform and/or self-administered intervention in either an abstract, an article, or clinicaltrials.gov.
Training of staff	Mentioning or description of training in how to access and/or react to patient-reported data in either an abstract or an article.
Self-management	Advice on symptom management is delivered to the patient either in a pre-distributed booklet or electronically.
Alerts to clinicians	Information sent to the healthcare provider based on changes and/or severity of the patients´ reports according to predefined thresholds.
Designated staff	Designated staff capacity with a clear delineation of responsibilities and expectations of team members, and a workflow allowing these activities.

Alerts to clinicians, designated staff, and training of staff

Most ESMO studies have utilized predefined symptom management alerts that prompted clinicians to take action when symptoms changed or worsened. In five of these studies, alerts were sent to clinicians when pre-defined thresholds were exceeded [10–14], allowing clinicians (often nurses) the possibility of contacting the patients to initiate supportive care, thereby alleviating symptoms or side effects. This was only true for one of the Danish studies [19], where a notification was sent to a clinical nurse who subsequently contacted the patients by phone to address potential clinical needs. The four Danish studies used the same digital platform (AMBUFLEX), while the ESMO studies employed various platforms (Table 1). The AMBUFLEX platform was found to be both flexible and highly user-friendly among Danish patients and healthcare professionals [20, 21], and could effectively be adapted to various patient populations and clinical aims [22].

The allocation of designated staff occurred in six of the interventions of the ESMO studies [8, 10–14], but only in one Danish study [19] (Fig. 1; Table 2). Only two ESMO studies [10, 13] and one Danish study [19] provide guidance on how clinicians should address new or worsening symptoms, which is why the effect of this factor on clinical outcomes remains unclear (Fig. 1; Table 2).

Patient involvement, health-related quality of life, and the patient experience

When patients take an active role in tracking and reporting their symptoms, they become more engaged in their healthcare. This involvement may lead to better adherence to treatment plans, a greater understanding of own health, and a stronger sense of control over managing disease and treatment. In four ESMO studies [10–13] and in three of the Danish studies [17–19, 23], the patients who were randomized to the PRO-intervention reported better health-related quality of life in varying degrees compared to standard care. In one ESMO study [14] and one Danish study [20], the patient experience/satisfaction was improved when using PROs, and one ESMO study reported higher self-efficacy in the PRO intervention group [10]. Overall, symptom monitoring with PROs can lead to improved clinical outcomes and better patient experiences, potentially serving as a crucial factor in improving cancer care across various diagnoses and specialties [1].

Perspectives

As stated in the ESMO guideline, there is no reason to delay the implementation of ePROs in oncology clinical care. The benefits are numerous [7], and the majority of patients are positive towards data collection using ePROs [24]. Moreover, not only in Denmark, with its tax-funded healthcare system, but in most countries, the healthcare systems face the dual challenge of a rising number of cancer patients and limited resources. In this scenario, ePROs appear to be an obvious solution, offering the potential to better clinical outcomes during cancer therapy and improve quality of life.

In the Danish studies, we demonstrated that most Danish RCTs investigating ePRO as an intervention during cancer therapy, compared to standard care, failed to show a significant impact on primary clinical outcomes. These trials often lacked key components such as designated staff capacity and adequate clinician training.

The absence of effects in the Danish studies aligns with a recent qualitative study from Norway, which highlights the importance of considering the diverse perspectives of healthcare practitioners and fostering inter-professional collaboration for the successful implementation of ePRO in oncology. The authors also emphasize the need for a shared understanding/interpretation of the importance of PROs [25].

Conclusion

The design of the various PROs, the selected digital platforms, integration in electronic health records, their relevance to specific patient populations and treatments, as well as the timing and management of their completion, are all factors that may influence the successful implementation of ePROs. However, our findings suggest that the clinical effectiveness of ePROs during cancer treatment may primarily be compromised when oncological care processes fail to use the structured input provided by PRO. In our view, this underuse may stem from limited knowledge about PRO or a lack of resources, such as the absence of designated staff to monitor the patient reports regularly. Further, if financial support is missing, implementation may be challenged. Thus, implementing ePROs in oncology care may initially require a clear hospital vision [26] and additional resources, but these investments may be worthwhile. In the long run, the utilization of ePROs may enable more accurate symptom monitoring, allowing for early identification of issues such as pain, fatigue, or mental health concerns, which can lead to timely interventions and improved patient outcomes. Therefore, an initial investment in resources is required when implementing ePROs, including the design and preparation phase [27], training for both patients and healthcare providers [26], and most importantly, designated staff responsible for directly handling the PROs as seen in the study by Franzoi et al. [5]. Their involvement ensures proper monitoring, feedback to patients, and improved supportive care. This dedicated attention seems key to achieving the efficiency and patient-centered care that ultimately benefits both the patients and the healthcare system.

Authors’ contributions

Design of the study: LKT and HP. Data analysis: LKT, ILR, and HP. Manuscript writing: LKT, ILR, and HP. Final approval: LKT, ILR, and HP.

Funding

The study has received no funding.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.