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Abstract
Introduction Symptom management is crucial in cancer care, yet patient symptoms are often overlooked in routine care. There is some evidence that electronic symptom monitoring and management can improve patients’ physical function, symptom control, quality of life and survival outcomes. However, the evidence of the impact on survival outcomes in patients with advanced cancer is still limited and debated. This study aims to conduct a prospective randomised controlled trial by a professional symptom management team to monitor and manage symptoms in advanced cancer patients via an electronic information systems for patient-reported outcomes (ePRO) system (WeChat mini-program) and to verify its effectiveness on improving overall survival.
Methods and analysis This is a single-centre, prospective, open-labelled, randomised, parallel-controlled clinical trial targeting patients with advanced cancer. We plan to recruit 940 patients using a stratified block randomisation method based on different tumour types. The control group will receive a symptom management self-care manual (both electronic and paper versions). Similarly, the intervention group will receive the same manual and education while also received symptom management by the hospital’s specialised symptom management team through the ePRO system. The primary outcome is comparison of overall survival between groups at the 24-month follow-up. Secondary outcomes will include quality of life, psychological status and incidence of adverse events.
Ethics and dissemination The study protocol and related documents received approval from the Ethics Committee of Peking University Cancer Hospital (IRB) in December 2023 (2023YJZ99). Ethical approval will be obtained before implementing any major study revisions in the future. The results of this study will be disseminated through academic seminars, peer-reviewed publications and academic conferences.
Trial registration number ChiCTR2400081247.
- ONCOLOGY
- PALLIATIVE CARE
- Patient Care Management
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Strengths and Limitations of this Study
Use of a widely accessible electronic information systems for patient-reported outcome system: The study leverages a WeChat mini-programme for real-time data collection, which could enhance patient engagement and data collection efficiency.
Randomised controlled design: This approach minimises biases and provides a robust framework for comparing outcomes between the intervention and control groups.
Stratified block randomisation: This method helps ensure balanced allocation of participants based on tumour types, enhancing the internal validity of the study.
The single-centre design limits the study’s generalisability, and the open-label nature may introduce biases.
Introduction
Symptom management is an indispensable component of cancer care. Cancer patients often experience various symptoms related to the disease and its treatment,1 2 which increase their suffering and the risk of complications.3 4 However, during standard clinical cancer care, patients’ symptoms often do not receive sufficient attention or timely management.5–7 Interventions aimed at monitoring and managing symptoms can improve clinical outcomes for patients undergoing cancer treatment. Using electronic information systems for patient-reported outcomes (ePRO), including the internet, mobile apps or automated telephone services, for symptom monitoring is entirely feasible for identifying cancer symptoms and addressing them by clinicians.8 There is a growing interest among scholars in integrating ePRO symptom monitoring into routine oncology practice, yet studies demonstrating its clinical benefits, particularly in survival, remain relatively limited.9
A randomised controlled trial conducted among patients with advanced non-progressive stage IIA to IV lung cancer showed that the median survival was significantly longer in the web-based symptom monitoring group compared with standard clinical follow-up (22.5 months vs 14.9 months, HR 0.59, 95% CI: 0.37 to 0.96, p=0.03).10 11 Another single-centre, randomised controlled trial conducted from 2007 to 2011 among patients with metastatic solid tumour undergoing chemotherapy found that the median survival in the PRO intervention group (31.2 months, 95% CI: 24.5 to 39.6) was significantly longer than in the standard treatment group (26.0 months, 95% CI: 22.1 to 30.9, p=0.03). Even after adjusting for other variables using a multivariate model, the difference remained statistically significant (HR 0.83, 95% CI: 0.70 to 0.99, p=0.04).12 13 Based on these single-centre clinical study findings, researchers conducted a multicentre randomised controlled trial (the PRO-TECT trial) across 52 community oncology centres in the USA to evaluate whether electronic symptom monitoring could improve survival, quality of life14 and other clinical outcomes for treated cancer patients, although the primary outcome of overall survival has yet to be reported. In previous studies, the ePROs systems often relied on web-based platforms, which required patients to actively log in, navigate through menus and manually input their symptoms. WeChat provides a platform that is both intuitive and convenient for patients. Unlike traditional electronic systems, WeChat does not require patients to download additional applications or create new accounts, significantly reducing barriers to use.
Therefore, we plan to conduct a prospective, randomised controlled trial to verify the effectiveness of the hospital symptom management team using the ePRO system (WeChat mini-programme) in providing specialised symptom monitoring/management for patients with advanced cancer compared with standard clinical care in improving overall survival.
Methods and Analysis
We used the SPIRIT reporting guidelines to ensure the transparent and comprehensive reporting of our study protocol,15 including key elements such as the study design, objectives, interventions, outcomes and statistical methods. The recruitment for this study began on 18 March 2024 and is expected to conclude by December 2027.
Primary objective
To compare the overall survival (2-year overall survival (OS)) of patients with advanced cancer in the intervention group (ePRO symptom monitoring management) vs the control group (standard treatment).
Secondary objectives
To compare the physical function scores of advanced cancer patients in the intervention group with control group as measured by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30).
To compare the overall health status/quality of life of advanced cancer patients in the intervention with control groups as measured by EORTC QLQ-C30.
To compare the symptom burden scores of advanced cancer patients in the intervention with control groups as measured by EORTC QLQ-C30.
To compare the individual symptom scores (fatigue, nausea and vomiting, pain, dyspnoea, insomnia, appetite loss, constipation, diarrhoea) of advanced cancer patients in the intervention with control groups as measured by EORTC QLQ-C30.
To compare the psychological and emotional status of advanced cancer patients in the intervention with control groups.
To compare the completion rate of chemotherapy between advanced cancer patients in the intervention with control groups.
To compare the number of emergency visits between advanced cancer patients in the intervention with control groups.
To compare the incidence of adverse events between advanced cancer patients in the intervention with control groups.
Study design
This is a prospective, randomised, parallel-controlled clinical trial to validate the effectiveness of ePRO-based symptom monitoring management on improving survival in patients with advanced cancer (see figure 1). The primary assessment is to evaluate whether the hospital symptom management team, using the ePRO system (WeChat mini-programme), can provide specialised symptom monitoring/management that improves overall survival compared with the standard clinical treatment group (where control group patients only receive a symptom management reference manual).
Trial flow diagram.
During the follow-up period, participants will be monitored at 1, 3, 6, 9, 12, 18 and 24 months, or until the study is terminated, to collect data on survival, EORTC QLQ-C30 scores, psychological and emotional status, completion of cancer treatment, number of emergency visits, and adverse events.
Patient screening and recruitment
Selection of study subjects
Inclusion criteria
Age ≥18 years;
Diagnosed with advanced/late-stage cancer;
Outpatients currently receiving non-curative or palliative systemic cancer treatment, including chemotherapy, targeted therapy or immunotherapy;
Expected survival of more than 3 months, with eligibility for enrolment at any point during the treatment process or cycle;
Being able to complete symptom reporting via the ePRO system (WeChat mini-programme) independently or with family assistance;
Voluntary participation in the study and signing of an informed consent form.
Exclusion criteria
Comorbid severe mental disorders (eg, severe depression, schizophrenia) or cognitive impairments that prevent cooperation in completing the study;
Patients undergoing curative treatments (eg, adjuvant chemotherapy for breast cancer);
Hormonal therapy as the only treatment option (eg, androgen deprivation therapy for prostate cancer);
Indolent or slowly progressing lymphomas;
Non-solid tumours, including leukaemia, gliomas, etc;
Participation in other clinical trials;
Any other condition that the investigator believes may interfere with the evaluation of efficacy.
Randomization
This trial employs a stratified block randomisation method, categorising participants based on different tumour types. Central randomisation will be conducted using an electronic interactive web response system (IWRS) provided by Peking University Clinical Research Institute, randomising subjects into either the intervention group or the control group in a 1:1 ratio. A statistician not involved in the clinical trial uses SAS statistical software to generate random numbers and group information through the stratified block randomisation method, producing random seed numbers and results that are stored as blind data. The RedCap system at Peking University Clinical Research Institute automatically assigns random numbers and groups, while research centre staff enter participants’ basic information (initials, age, gender, subject number, etc) into the web-based central randomisation system (RedCap). The system will automatically generate random IDs and subject IDs according to the aforementioned principles and will inform the researchers via the web of whether a participant is assigned to the intervention or control group. Once researchers receive the randomisation results, they will provide the corresponding interventions based on the assigned group.
This trial’s intervention is based on ePRO symptom monitoring management, and blinding is not feasible, making it an open-label clinical trial where both researchers and participants are aware of the group assignments and the interventions received.
Intervention
Control group
Control group patients will receive a symptom management reference manual (both electronic and paper versions), which is based on the most reliable evidence, current guidelines and expert consensus, along with health education and training on how to use the manual for symptom management.
Intervention group
Besides receiving the same symptom management reference manual (both electronic and paper versions) with the control group and health education and training on how to use it. The hospital’s symptom management team will provide specialised symptom management and intervention based on the ePRO system (WeChat mini-programme) for cancer patients (see figure 2). This primarily includes patient reports through the WeChat mini-programme, symptom interventions from the clinical symptom management team based on ePRO, and treatment decision support from oncologists.
Symptom management team based on eRPO symptom management and intervention.
Weekly ePRO reporting via WeChat mini-program
Patients in the intervention group will self-report symptoms weekly through the WeChat mini-programme for 1 year after randomisation. This reporting will occur at a fixed time on a designated day each week and include symptoms such as pain, nausea, vomiting, constipation, diarrhoea, shortness of breath, insomnia, depression, dietary conditions, physical status (ECOG), falls and financial difficulties (see online supplemental appendix 1) from the National Cancer Institute’s Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) validated item library.16 The WeChat mini-programme will remind patients to complete their symptom reports on a weekly basis.
Supplemental material
Follow-up on incomplete PRO surveys
If patients do not complete their weekly reports within 24 hours, they will receive continuous reminders from the system (the WeChat mini-programme will send reminders every 8 hours). If the survey remains incomplete after 48 hours, the follow-up staff will contact them via phone. They will ask questions verbatim and input the responses into RedCap (noted as an interview conducted). Family members, caregivers or follow-up staff may assist patients with completing the system reports.
Real-time ePRO reporting
In addition to the scheduled weekly reports, patients can also self-report relevant symptoms in real-time via the WeChat mini-programme if their symptoms got worse, or poorly controlled, or if new severe symptoms arose, particularly when consultation or guidance from clinical staff (symptom management team) is needed.
Clinical symptom management team based on ePRO
The symptom management team involved in this study will receive evidence-based symptom management pathways, provided in paper and/or electronic formats.
When any symptom score reaches or exceeds a predefined level, or if there is a progression/deterioration compared with the previous week that reaches an alert threshold, or if symptoms are reported outside of the fixed reporting times, the WeChat mini-programme will ‘automatically trigger’ targeted health education materials and scientific advice to guide patients in self-managing their symptoms.
Simultaneously, an automatic ‘electronic alert’ will notify designated symptom management team members, along with evidence related to symptom management pathway recommendations. The symptom management team must take action within 48 hours to respond promptly:
Review previous ePRO report results, analyse the patient’s ePRO trajectory and develop an initial ‘clinical prescription’ based on the tumour patient symptom management standard operating procedure.
Contact the patient to provide professional consultation and self-care advice, offering non-pharmacological interventions (such as dietary changes, exercise, psychological therapy, etc) or pharmacological treatments as necessary.
This study will only monitor (ePRO) and manage symptoms in cancer patients without intervening in the clinical treatment plans for cancer. The treatment plan will be determined by the oncology clinical staff based on clinical guidelines, taking into account the patient’s condition and recommendations from the symptom management team. The symptom management team consists of doctors from the hospital’s symptom management outpatient clinic, with clinical expertise in managing common physical symptoms and psychological distress in cancer patients.
Data collection and management
After obtaining informed consent from the study participants, baseline data will be collected through interviews, medical record reviews, and physical examinations and self-reporting. This includes the following items: demographic information, clinical tumour characteristics, treatment plans, EORTC QLQ-C30 scale, and psychological status assessments: PHQ-9 and GAD-7.
Training system usage
Common process for control and intervention groups
At baseline, all participants will be trained on how to use the online system to complete study questionnaires.
All participants will complete the baseline questionnaire and follow-up questionnaires at 1, 3, 6, 9, 12, 18 and 24 months or at the end of the study (±7 days).
Participants will be informed that their caregivers can assist them in any preferred manner. Clinical research assistants (CRAs) can provide technical support. If participants cannot complete the questionnaire, they can designate a caregiver to do so on their behalf. If the participant/caregiver does not complete the questionnaire on time, the CRA will contact them to collect the information (which will then be input into the RedCap system).
It is preferable for the baseline questionnaire to be completed with technical support from the CRA before the participant leaves the clinic.
At each follow-up time point, participants will receive a reminder about the upcoming questionnaire, emphasising its importance and offering assistance.
Additional process for the intervention group
At baseline, participants will also be trained on how to report symptom burden, economic burden and physical function via weekly PRO for 12 months.
Training will include the operation of real-time symptom alerts.
Participants will complete reports online with weekly reminders.
Participants will be informed that if they cannot complete the questionnaire as scheduled, they and/or their designated caregivers will receive a phone call from the research team.
Participants should be informed that even with real-time alerts, the symptom management team may not respond immediately.
Participants should be informed that they cannot rely solely on this system; if symptoms are severe or urgent, they should consider contacting their physicians directly or going to the emergency room.
Safety reporting
This study will collect the following safety information, which will be recorded in the eCRF: intervention-related adverse events and serious adverse events (SAEs). Definitions and procedures related to these events are as follows. If a suspected unexpected serious adverse reaction occurs during the study that is related to the intervention, appropriate treatment measures will be taken immediately, and follow-up will be conducted.
All unexpected serious adverse events must be documented in detail by the investigator on knowledge of the event, including the time of occurrence, severity, duration, relatedness assessment, measures taken and outcomes, and reported to the ethics committee in a timely manner.
Sample size calculation
The primary outcome indicator for this study is the 2-year OS. Based on previous clinical studies, the HR for the intervention group compared with the control group is estimated to be 0.70, with an average median survival of 10 months for patients with advanced cancer. Based on these assumptions, a two-sided significance level of 0.05 and a power of 1-β=0.80 were set, with a patient ratio of 1:1 for the trial and control groups, accounting for a 15% dropout rate. The calculated sample size is 940 participants, with 470 in each group.
The primary outcome indicator for this study is the 2-year OS. Based on previous clinical studies, the HR for the intervention group compared to the control group is estimated to be 0.70, with an average median survival of 10 months for patients with advanced cancer. Based on these assumptions, a two-sided significance level of 0.05 and a power of 1-β=0.80 were set, with a patient ratio of 1:1 for the trial and control groups, accounting for a 15% dropout rate. The calculated sample size is 940 participants, with 470 in each group.
This trial will conduct an interim analysis when the number of followed-up participants reaches 50% of the total sample size (470). The interim and final analysis will use the O’Brien-Fleming spending function method to adjust the significance level, corresponding to two-sided levels of 0.0054 and 0.0492. If the interim analysis indicates a statistically significant difference, the trial may be terminated early due to the achievement of the expected effect. If the efficacy difference between the two groups is not statistically significant, the sample size will be re-estimated based on the parameters from the interim analysis to determine the final sample size.
Data analysis plan
Quantitative data that follow a normal distribution will be described using means±SD, while non-normally distributed quantitative data will be described using medians and interquartile ranges (Q1, Q3). Categorical data will be described using frequencies and percentages.
Hypothesis testing in this study will compare the two groups. For normally distributed quantitative data, independent samples t-tests will be used for inter-group comparisons, while Wilcoxon rank-sum tests will be used for non-normally distributed quantitative data. Categorical data comparisons will employ χ2 tests or Fisher’s exact probability method. For ordinal data, Wilcoxon rank-sum tests will be used.
All statistical tests will be two-sided unless otherwise specified, with a significance level of p<0.05 (two-sided) considered statistically significant.
Interim analysis
This study employs an adaptive design to determine the final sample size. An interim analysis will be conducted after 50% (470) of the study participants have been enrolled and the primary outcome indicators have been followed up, analysing the OS for each group at 2 years. Based on the interim analysis results, the sample size will be recalculated to serve as the final sample size for this study. However, due to the expected good safety profile of the intervention used in this study, there are no plans for early termination; thus, the interim analysis will not conduct hypothesis testing or statistical analysis for the intervention effect, and the significance level will not be adjusted.
Monitoring
The project coordinator is responsible for monitoring this study to ensure that the trial implementation, data recording and analysis comply with the study protocol and relevant regulatory requirements. The coordinator will complete monitoring visits to the research centre according to a pre-established monitoring plan, which may be conducted as on-site or remote visits. After each visit, the coordinator will prepare a written monitoring report and submit it to all relevant parties involved in project management according to the monitoring plan.
Patient and public involvement statement
Patients or the public were not involved in the design, or conduct, or reporting, or dissemination plans of our research.
Ethics and dissemination
The study protocol and related documents received approval from the Ethics Committee of Peking University Cancer Hospital (IRB) in December 2023 (2023YJZ99). Ethical approval will be obtained before implementing any major study revisions in the future. The results of this study will be disseminated through academic seminars, peer-reviewed publications and academic conferences.
Discussion
The proposed study marks a significant advancement in integrating ePRO systems into routine cancer care, particularly for patients with advanced cancer. The use of a WeChat mini-program for symptom monitoring is innovative and leverages a widely used platform in China, enhancing user engagement and data collection efficiency. Focusing on overall survival as the primary outcome is crucial, as it directly addresses the ultimate goal of cancer treatment.
However, the study’s single-centre design and open-label nature are limitations that must be acknowledged. Future studies could consider multicentre designs to enhance the generalisability of the findings. Additionally, employing blinding or objective outcome measures could help mitigate biases associated with the open-label design.
The study’s reliance on technology presents both opportunities and challenges. While the WeChat mini-program offers a convenient and accessible tool for symptom reporting, it is essential to ensure that all participants, regardless of their technological proficiency, can effectively use the system. This may require additional support or alternative methods for those less comfortable with technology.
The open-label design introduces potential bias since both participants and researchers are aware of group assignments and interventions. However, this design reflects real clinical settings where patients and providers are aware of interventions. The potential for enhanced care in the intervention group is a key way ePRO systems are thought to improve outcomes.
The study uses stratified randomisation to balance tumour types between groups. We acknowledge that tumour heterogeneity may affect ePRO effectiveness, so subgroup analyses will assess ePRO differences across tumour types (eg, lung cancer, metastatic breast cancer). Future research can explore ePRO’s applicability for different tumours and optimise its use for better patient outcomes.
Furthermore, the planned interim analysis is a strength, allowing for adjustments to the sample size based on preliminary data. This adaptive design can increase the efficiency of the trial and provide valuable insights into the intervention’s effectiveness earlier in the study process.
We recognise that cultural, economic and policy backgrounds may vary, influencing the provision and reception of medical services. However, we believe that systematic management of patient self-reported symptoms can lead to better patient engagement and health management across different healthcare systems. The universality of this approach will help promote and apply the ePRO system globally, thereby improving the overall health and quality of life for cancer patients.
Overall, the study has the potential to contribute valuable evidence on the effectiveness of ePRO-based symptom monitoring and management in improving survival outcomes for patients with advanced cancer. Its findings could inform future research and practice, ultimately leading to better symptom management and improved patient outcomes in oncology care.
Trial status
The randomised controlled trial is now in an active recruitment phase.
Ethics statements
Patient consent for publication
Acknowledgments
The authors are grateful to the clinicians who are integral to this study.
References
Footnotes
LT and YH contributed equally.
Contributors Writing of original protocol, YH and YP; writing of original manuscript, YH and YP; review and editing of manuscript draft, LT, ZL, YW, YZ, ZS and LS; supervision, LT; funding procurement, LT; LT is responsible for the overall content as guarantor; all authors have read and agreed to the published version of this manuscript.
Funding This project has received funding from the China Association of Gerontology and Geriatrics (no grant number).
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.