Effects of an Electronic Patient Reported Outcome Measures (e-PROMs) Program on Symptom Reporting, Use of Healthcare, and Overall Survival in Patients With Lymphoma: A Multicenter Prospective Study.

Introduction

Current models of care for specialties such as oncology are shifting from a disease‐centered to a patient‐centered approach [ 1 ]. While decisive advances have been made in terms of new treatments and survival, there is still much room for improvement regarding other aspects of health such as symptom management, functional status, and health‐related quality of life (QoL) [ 2 ]. To implement effective changes, it is crucial for healthcare providers to obtain reliable data on outcomes that truly matter to patients [ 3 ].

Patient‐reported outcomes (PROs) are reports of health status or QoL directly provided by patients, without interpretation by third parties including clinicians [ 2 ]. PROs provide a unique and valuable source of information and are usually assessed via patient‐report outcome measurements (PROMs); validated tools in the form of questionnaires. PROMs data collection is becoming a routine practice in clinical trials and has been shown to improve patient management and overall survival (OS) [ 4 ]. Regulatory agencies, such as the Food and Drug Administration (FDA) highlight the importance of PROs in real‐world evidence generation as they complement data obtained through traditional, clinician‐focused parameters [ 5 ]. Although some specialties such as orthopedics have started to implement PROM programs to gather information on health‐related QoL before and after joint replacement [ 6 ], the use of PROMs in routine oncology practice is still uncommon [ 7 ].

Recent developments in health informatics and systems infrastructure have opened the door to widespread use of electronic PRO programs (ePROs). Both patients and healthcare providers can benefit from harnessing the potential of e‐health tools to facilitate individual‐level treatment decisions and encourage patient participation in oncology care [ 8 ]. Healthcare professionals tend to underestimate the incidence and severity of treatment‐related adverse events (AE) reported by their patients, and ePROs have shown to improve speed of reporting and assessment of AEs [ 9 , 10 , 11 ].

We present the results of a multicenter prospective observational study including patients participating in an e‐PRO program, “E‐Res Salud” for hematological malignancies over an 18‐month period in Madrid, Spain.

Methods

Study Design

We conducted a prospective observational cohort study of patients with Hodgkin and non‐Hodgkin lymphoma receiving treatment at four Spanish hospitals, comparing patient‐ and clinician‐reported patient outcomes in a cohort of patients participating in an online PROMs program. We also aimed to assess the effects of the program on different clinical outcomes.

Setting

The Quirónsalud 4‐H Network is a privately managed hospital network in Madrid, Spain, serving a population of over 1 million people through four hospitals (Fundación Jiménez Díaz University Hospital, Infanta Elena University Hospital, Rey Juan Carlos University Hospital, and General Villalba University Hospital). “E‐Res Salud” is the Quirónsalud 4‐H Network's value‐based digital healthcare program which collects individual and aggregated e‐PROs to improve healthcare process management and patient experience, and to include patients in the healthcare decision‐making process [ 12 ]. E‐PROMs questionnaires are sent out automatically to participating patients over a web application, the Patient Portal, at specific timestamps throughout the patient journey.

Intervention and Data Collection

“E‐Res Salud” was launched in January 2020 for patients with selected clinical conditions, including hematological malignancies (lymphoma and multiple myeloma). PROMs questionnaires included in the “E‐Res Salud” program for patients with hematological malignancies were aimed at assessing QoL, symptoms, and treatment‐related AEs using the EuroQoL‐5D, HM‐PRO, and PRO‐CTCAE surveys, respectively. EuroQoL‐5D and HM‐PRO questionnaires were sent out every 3 months from diagnosis for all participating patients, including those who had not started treatment. The PRO‐CTCAE questionnaire was sent to patients on a monthly basis during treatment, and 3 and 6 months after finishing treatment.

The PRO‐CTCAE measurement system was developed by National Cancer Institute (NCI) as a companion to the CTCAE (Common Terminology Criteria for Adverse Events) and consists of 124 items representing 78 symptomatic AEs drawn from the CTCAE [ 13 ]. Each item evaluates an aspect of a given symptom, for example frequency, severity, interference, amount, or presence/absence. The items are clustered in 14 categories and evaluated using a five‐point scale.

A group of expert physicians from the network's four hematology departments selected 17 items from the PRO‐CTCAE survey to create a decision algorithm. Patients reporting high‐intensity symptoms for these items would trigger an alert system over the Patient Portal, and a specialist nurse practitioner from the hematological care team would contact the patients via telephone within the next 24 h. Patients reporting low‐intensity symptoms for the 17 selected items would receive automatic, standardized recommendations following current clinical guidelines over the Patient Portal.

Demographic and clinical variables were collected manually from the network's EMR, Casiopea (Inetum), and included age, sex, therapy schema, Eastern Cooperative Oncology Group performance status (ECOG), and line of treatment. For this study, patients' responses to the PRO‐CTCAE questionnaire were collected after the 1st, 3rd, and 6th months of therapy.

Participants

We included lymphoma patients receiving outpatient intravenous therapy at the network's four hospitals between January 1, 2020, and June 30, 2022. Patients receiving inpatient immunochemotherapy or presenting early mortality (after a single course of therapy) were excluded. All participating patients were registered for the Patient Portal application. Patients declining to participate in the program were considered the control arm.

Outcomes

The study's primary objective was to compare AEs reported by physicians in the electronical medical record (EMR) and those reported by patients through a validated questionnaire (PRO‐CTCAE). Secondary objectives were to describe the evolution of symptoms reported during treatment period and to analyze the effects of the “E‐Res Salud” program for hematological malignancies on the use of healthcare resources (emergency department visits and unscheduled hospital admissions), adherence to treatment, and OS.

Follow‐Up

Patients were followed for a minimum of 6 months after starting treatment, with a median of 19.1 months of follow‐up (11.4–26.3). PROM surveys were administered at months 1, 3, and 6. Control patients were followed using EMR documentation only.

Ethics

This study was conducted in accordance with the declaration of Helsinki. An independent institutional ethics committee approved the study protocol (EO103‐21_FJD).

Statistical Analysis

Results were reported as median (interquartile range), or absolute frequency (percentage) based on the nature of the variables. Differences in proportions were compared with a two‐sided chi‐square test and differences in means or medians with a two‐sided Student's T ‐test. Survival was estimated with Kaplan Meier method, with confidence intervals (CI) and p values estimated using a double‐sided log rank test. A p value of less than < 0.05 was considered statistically significant. Analyses were performed with SPSS‐Statistics v.23.

Results

Of the patients starting first or subsequent lines of treatment for lymphoma at the four hospitals, 243 could finally be enrolled in the study. Median follow‐up was 19.08 months (range, 0.92–36.83). Overall, 121 patients (49.8%) participated in the “E‐Res Salud” program for hematological malignancies, and 122 (50.2%) patients declined to participate and were considered the control group. Baseline demographic and clinical characteristics of patients from both groups are presented in Table 1 . In the overall patient population, median age at diagnosis was 62 years (IQR 51–73), and 54 (22.2%) were aged 75 years or older. Most patients had a baseline ECOG (Eastern Cooperative Oncology Group) performance status of 0–1 (186, 76.5%).

Nearly half of patients (98, 40.3%) presented a diagnosis of diffuse large B cell lymphoma (DLBCL). Other frequent diagnoses included follicular and Hodgkin lymphoma. Treatment regimens are also summarized in Table 1 ; R‐CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone) was the most common regimen (111, 45.7%). Most patients (211, 86.8%) were receiving their first line of therapy. Although patients were not randomized, no significant differences regarding age, sex, baseline performance status, and line of treatment were observed. The only significant difference between groups was the proportion of patients receiving R‐CHOP (68 (56.2%) in the participating group and 43 (35.2%) in the non‐participating group, p = 0.027).

Safety

Clinician‐reported AEs were collected manually from the EMR, while patient‐reported AEs were collected directly from the PRO‐CTCAE questionnaire. In order to compare AEs reported by both groups (clinicians and patients), we standardized terminology according to PRO‐CTCAE items.

Figure 1 presents Pareto charts showing the incidence of the different AE categories reported by patients and clinicians. The top five clinician‐reported AE groups were gastrointestinal (154, 63%), neurological (70, 29%), pain‐related (68, 28%), skin (64, 26%), and oral AEs (53, 22%). In contrast, the five most frequent patient‐reported AE groups (reported as high/very high frequency, severity, or interference) included gastrointestinal (82, 68%), skin (82, 68%), oral (61, 50%), sleep‐related (61, 50%), and pain‐related AEs (56, 46%). The only groups where no differences were found between clinician and patient‐reported AEs ( p > 0.05) were gastrointestinal (63% vs. 68%), neurological (29% vs. 31%), and respiratory AEs (12% vs. 17%). In contrast, cutaneous, oral, and sleep‐related symptoms were reported by more than 50% of patients, but were recorded by only 26%, 22%, and 19% of clinicians in the EMR ( p < 0.05).

Changes in PROMs score reports from baseline to the end of therapy were also analyzed. A slight tendency toward higher rates of AE toward the end of therapy was observed, without reaching statistical significance (Figure 2 ). A total of 66 patients (54.5%) reported high‐grade AEs during the first course of therapy, with 66.1% and 67.8% of patients reporting high‐grade AEs after the third and sixth course of therapy, respectively.

Use of Health Resources and Adherence to Treatment

Fewer emergency department visits were observed among patients participating in the “E‐Res Salud” program for hematological malignancies compared to those who declined to participate (37.2% vs. 56.6%; p < 0.01). Lower rates of unscheduled hospital admissions (21.5% vs. 32.8%; p < 0.05) were also observed for the participating group.

Patients participating in the PROMs program presented higher rates of treatment completion (94.2% vs. 83.6%; p < 0.01). No differences in dose reductions (14.2% vs. 18.0%; p = 0.41) and treatment delays (26.9% vs. 32.0%; p = 0.39) were found between both groups.

Overall Survival

After a median follow‐up of 19.1 months (IQR 11.5–26.3), median OS was not reached in either group. However, median OS was significantly higher for patients participating in the “E‐Res Salud” program for hematological malignancies than for non‐participants (88.4% vs. 79.5% after 18 months of follow‐up; stratified hazard ratio, 2.30; 95% CI, 1.25–4.22; p = 0.007). The results of survival analysis are presented in Figure 3 .

Discussion

Advancing toward value‐based cancer care will require a major transformation of the current system, in which PROs are set to play an increasingly important role [ 14 ]. Our study reports the implementation of an e‐PROMs program, “E‐Res Salud” for hematological malignancies, across four teaching hospitals, and compares AE reporting by clinicians and patients. We found that AE reporting differs significantly between patients and healthcare professionals. In addition, we evaluated the use of health resources, adherence to treatment, and OS, comparing patients participating in the program and non‐participants. We found that patients participating in “E‐Res Salud” showed significantly lower rates of emergency department visits and unplanned hospital admissions, as well as significantly higher rates of treatment completion and OS.

PROMs are valuable tools for assessing different aspects of patients' perceived health, such as QoL or symptom burden. QoL assessment informs clinicians of patients' overall well‐being and aids evaluation of functional and psycho‐social impairment during therapy [ 15 ]. Furthermore, QoL data have been shown to be of prognostic value regarding therapeutic outcomes of specific hematological diseases and may help to guide treatment selection [ 16 ]. PROMs can improve communication between patients and healthcare professionals, optimize evaluation of treatment‐related AEs, and promote shared decision making [ 2 ]. PROMs have demonstrated value in detecting unreported AEs and psychosocial alterations that are often missed in routine clinical visits [ 17 ], and are increasingly recognized as prognostic tools in lymphoma, with studies demonstrating that impaired baseline QoL is associated with shorter progression‐free and OS [ 18 ]. Moreover, recent research suggests that PROMs may be especially valuable for lymphoma survivors, who frequently experience late AEs such as fatigue, anxiety, and cognitive dysfunction [ 19 , 20 ]. PROMs could also add value in the palliative care setting for relapsed/refractory lymphoma, where symptom control and patient preferences are the objective of care [ 21 , 22 ]. Available evidence supports PROMs collection in routine oncological practice and in clinical trials [ 14 ]. However, recent systematic reviews conclude that despite obvious benefits, PROMS are only fully reported in around 25% of lymphoma clinical trials [ 23 , 24 ]. Difficulties with incorporating PROMs in clinical trials for patients with lymphoma include the fact that repeated assessments over long or complex treatments may increase patient burden and lead to low completion rates [ 25 ]. At the same time, low‐health literacy, fatigue, and symptom severity can exacerbate missing data and skew results, with sicker patients being less likely to respond [ 26 ].

Despite several publications which highlight the importance of gathering PROMs in patients with hematological diseases [ 2 , 27 , 28 ], few examples of routine PROM assessment in lymphoma treatment have been reported. To be successful, PROs programs must be designed correctly to facilitate patient participation. The European Hematology Association (EHA) has released Guidelines for Patient‐Reported Outcomes in Hematology to aid healthcare providers when implementing PROs in routine care [ 29 ]. The “E‐Res Salud” program is a web‐based system which allows patients to report outcomes over a mobile app, as smartphones are an accessible, low‐cost method for measuring patients' symptoms in real time. This allows specialist nurses to contact patients promptly as soon as high‐intensity symptoms are reported. Our results show that implementing PROMs into the routine care of patients with lymphoma was associated with lower healthcare use and increased OS when compared to the current standard of care. We hypothesize that early responsiveness to patients' symptoms and higher rates of treatment completion could be responsible for the improved outcomes present in the group of patients participating in the “E‐Res Salud” program.

Patient response rate was around 50% in our study, similar to that of another study in lymphoma patients using an e‐PROMs tool [ 30 ]. Our findings demonstrate that, in line with recent research, patients detect severe, treatment‐related AEs sooner than healthcare providers [ 31 ]. This may be partly due to underlying heterogeneities in the way that clinicians collect and report AE‐related information. If clinicians do not explicitly ask after a given symptom, patients may not report AEs, leading to an infra‐estimation of the true incidence of AEs.

The strengths of our study are the large sample size, the existence of a control group, and the use of validated PROMs questionnaires. However, this study has several limitations. First, only patients with a diagnosis of lymphoma were included. The reproducibility of our results should be confirmed for patients with other hematological malignancies such as multiple myeloma, acute leukemia, and chronic conditions such as chronic lymphocytic leukemia or myeloproliferative neoplasms. Second, a selection bias may be present in our study as some hematologists from the four centers chose not to invite their patients to participate in the “E‐Res Salud” program, and because we excluded patients with more severe illness (those who received inpatient treatment and those with early mortality). A third potential cause of bias is the non‐randomized study design, which leads to the possibility that patients who agreed to participate were more likely to be open to the idea of e‐health tools and have less difficultly using them. Although we were unable to rule out this potential bias, no differences in age, sex, ECOG, or line of treatment were found between the group of patients participating in the “E‐Res Salud” program and non‐participating patients. However, we acknowledge that significant differences in the proportion of patients receiving R‐CHOP mean that this study fails to address the effect of different treatments on the probability of suffering AEs, and further, randomized studies are needed. Finally, if long intervals existed between the completion of a PROMs questionnaire and a patient's next visit at the outpatient clinic, the effect of the program on healthcare decisions may have been irrelevant. However, due to the implementation of a real‐time alert system, high‐intensity symptoms reported over PROMs questionnaires led to prompt clinical evaluation.

In conclusion, better understanding of patient‐reported symptoms could aid physicians to develop individualized treatment plans. The reduction of emergency department visits and unscheduled hospitalizations affects survival and both direct and indirect costs. Further follow‐up and a larger sample size will allow us to provide further evidence supporting the use of PROMs in routine hematology care and will enable us to improve shared decision‐making by integrating patients as part of the clinical decision‐making process.

Author Contributions

Raúl Córdoba : conceptualization, methodology, writing – original draft, supervision. Marta del Olmo Rodríguez : investigation, validation. Sergio Ramos : investigation, validation, writing – original draft. Alberto López García : investigation, methodology, validation. Daniel Morillo : investigation, methodology, validation. María‐Angeles Pérez‐Sáenz : conceptualization, methodology, validation. Carolina Miranda : conceptualization, methodology, validation. Rafael Martos : investigation, methodology, validation. Laura Beltran : investigation, validation. Eva Castillo : investigation, validation. Antonio Herrero : conceptualization, software. Alvaro Gómez‐Meana : conceptualization, software. Bernadette Pfang : writing – original draft, writing – review and editing, validation. Jorge Short Apellaniz : supervision, writing – final draft. Javier Arcos‐Campillo : supervision, writing – final draft.

Ethics Statement

This study was conducted in accordance with the declaration of Helsinki. An independent institutional ethics committee approved the study protocol (EO103‐21_FJD).

Consent

Participating patients gave their informed consent to participate in the E‐Res Salud program.

Conflicts of Interest

The authors declare no conflicts of interest.

Acknowledgments

We would like to sincerely thank the carers, patients, and clinicians from the Fundación Jimenez Diaz University Hospital, Rey Juan Carlos University Hospital, Infanta Elena University Hospital, and Villalba General University Hospital for contributing to this project.

Data Availability Statement

The data used in this project are available from the corresponding author upon reasonable request.

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