Electronic Patient Reporting of Symptoms During Cancer Treatment

This is a cluster RCT at approximately 50 sites where randomization will occur in a 1:1 ratio at the site level (not at the individual patient level). Therefore, approximately 25 sites will be randomized to the PRO-TECT intervention arm (patient-reporting of symptoms), and approximately 25 sites will be randomized to the control arm (usual care delivery). Approximately 1200 patients will be enrolled. Specifically:

PROCEDURES AT ALL SITES (CONTROL SITES AND INTERVENTION SITES):

* Site staff (CRA and Nurse Champion required) will attend the site initiation webinar with UNC staff, including training for the PRO-Core online data management system and orientation to the symptom management guidelines.
* At enrollment, all participants will be given a booklet with patient-level symptom advice and a link to the content online.
* All participants will receive compensation for participation, mailed to them as gift cards by UNC.
* CRAs will train all participants how to complete outcomes questionnaires for the trial using the PRO-Core online system. Participants will be given a choice to complete these in clinic or from home online, or if necessary via paper in clinic (with the CRA entering the data into PRO-Core). If the patient does not self-complete this information, the CRA will contact them to collect the information and then enter it into PRO-Core. The outcomes questionnaires will be completed at baseline; and at month 1 (+/- 2 weeks); and at months 3, 6, 9, and 12/off-study (+/- 4 weeks each), and will be available in English, Spanish, or Mandarin Chinese. At each time point, the CRA will contact the participant to remind them about the upcoming questionnaire and offer help.
* Chart abstraction will be conducted by CRAs at baseline and at off-study for each participant, with data entered into the PRO-Core system. Date of death information will additionally be abstracted at 18 and 24 months, and possibly later per the UNC study team.
* CRAs will be asked to complete a feedback survey (entered by the CRA into the PRO-Core online system) and may be asked to participate in a brief telephone debriefing and/or site visit.
* Accrual will be monitored in a weekly teleconference between the UNC team and site CRAs.

ADDITIONAL PROCEDURES AT INTERVENTION SITES ONLY:

* At baseline, CRAs will also train patients to self-report symptoms and physical functioning using the PRO-Core system weekly for up to a year, with a choice to do this online or via an automated telephone system (patient choice), and a choice of English, Spanish, or Mandarin Chinese.
* Whenever a concerning symptom is reported, an automated "email alert" notification will be sent to the site CRA. The CRA will forward the email alert to the responsible clinical nurse (or other covering clinician) and CC the site's Nurse Champion. Within 72 hours, the CRA will document what action(s), if any, were taken by the nurse in response to the alert (entered by the CRA into a form in the PRO-Core system).
* A symptom report will be printed/generated by the site CRA whenever the patient has a clinic visit, and will be given to the oncologist and nurse caring for the patient.

• Patient Self-Reporting of Symptoms (Other): At baseline, CRAs will train patients to self-report symptoms and physical functioning weekly for up to a year, with a choice to do so online or via an automated telephone system. Whenever a concerning symptom is reported, an automated "email alert" notification will be sent to the site CRA. The CRA will forward the alert to the responsible clinical nurse (or other covering clinician) and CC the site's Nurse Champion. Within 72 hours, the CRA will document what action(s), if any, were taken by the nurse in response to the alert (entered by the CRA into a form in the PRO-Core system). A symptom report will be printed/generated by the site CRA whenever the patient has a clinic visit and will be given to the oncologist and nurse caring for the patient.
• Usual Care Delivery (Other): Patients receive routine cancer care delivery with no additional systematic monitoring of symptoms

Primary outcomes

• Overall Survival [24 months]: Unadjusted Kaplan-Meier estimated survival, based on administrative datasets and practice self-report/medical records.

Secondary outcomes

• Physical Functioning [Month 3]: Physical functioning was measured at the 3 month time point using the European Organisation for Research and Treatment of Cancer QLQ-C30 questionnaire. The QLQ-C30 is a widely used 30 item questionnaire with excellent measurement properties. Physical functioning was assessed via 5 items from the QLQ-C30 which generated a single score on a 0-100 point scale (higher scores are better). Mean changes from baseline were measured using the QLQ-C30 at 3 months and compared between arms with a linear combination of parameters from a general linear mixed model. Patients who completed the QLQ C30 at baseline and each follow up time point were categorized as improved on each outcome if their score increased by >/=5 points from baseline; worse if their score decreased by >/=5 points and otherwise as stable.
• Symptom Control [Month 3]: Symptom control was measured at the 3 month time point using the European Organisation for Research and Treatment of Cancer QLQ-C30 questionnaire. The QLQ-C30 is a widely used 30 item questionnaire with excellent measurement properties. Symptom control was assessed as a composite of 8 QLQ-C30 symptom scale scores on a 0-100 point scale (higher scores are better). Mean changes from baseline were measured using the QLQ-C30 at 3 months and compared between arms with a linear combination of parameters from a general linear mixed model. Patients who completed the QLQ C30 at baseline and each follow up time point were categorized as improved on each outcome if their score increased by >/=5 points from baseline; worse if their score decreased by >/=5 points and otherwise as stable.
• Health-related Quality of Life [Month 3]: Health-related quality of life was measured at the 3 month time point using the European Organisation for Research and Treatment of Cancer QLQ-C30 questionnaire. The QLQ-C30 is a widely used 30 item questionnaire with excellent measurement properties. Health-related quality of life was assessed as a composite of function and symptom scale scores on a 0-100 point scale (higher scores are better). Mean changes from baseline were measured using the QLQ-C30 at 3 months and compared between arms with a linear combination of parameters from a general linear mixed model. Patients who completed the QLQ C30 at baseline and each follow up time point were categorized as improved on each outcome if their score increased by >/=5 points from baseline; worse if their score decreased by >/=5 points and otherwise as stable.
• Patient Satisfaction/Communication [Month 3]: Patients in the ePRO arm were measured via Patient Satisfaction Questionnaire assessing comprehension of ePRO questions, usability of digital ePRO system, meaningfulness/relevance of ePRO questions, communication/actionability with care team, clinical utility of ePRO system and patient self efficacy. The number of patients analyzed is the number of patients who completed the questions. Some questions were not administered to all patients.
• Emergency Department Utilization [1 year]: Data for emergency department visits were obtained from data abstracted at each practice from the electronic medical record.

Sex: All, ages: 21 Years to any, accepts healthy volunteers

Inclusion Criteria:

1. Adults (21+) with metastatic cancer of any type (EXCEPT leukemia or indolent \[slow growing\] lymphoma)
2. Receiving outpatient systemic cancer treatment for non-curative/palliative intent, including chemotherapy, targeted therapy, or immunotherapy.
3. Enrolled at any point in their treatment trajectory, meaning during any line of treatment, and at any point during a course or cycle of treatment.
4. Can understand English, Spanish, and/or Mandarin Chinese.

Exclusion Criteria:

1. Cognitive deficits that would preclude understanding of consent form and/or questionnaires.
2. Current participation in a therapeutic clinical trial (because these often involve PRO questionnaires and intensive monitoring).
3. Patients being treated with curative intent (e.g., adjuvant chemotherapy for breast, lung, or ovarian cancer; primary curative therapy for testis cancer or lymphoma).
4. Receiving hormonal therapy only (e.g., tamoxifen or aromatase inhibitors in breast cancer; androgen deprivation therapy in prostate cancer; or octreotide in neuroendocrine cancers)
5. Indolent lymphomas (due to their prolonged time courses that may be minimally symptomatic).
6. Leukemias (time courses inconsistent with other tumor types in chronic and acute leukemias).
7. Does not understand English, Spanish, or Mandarin Chinese.

Participant flow

Outcome results

• Overall Survival (Primary), Number, percentage of participants: ePRO Intervention 42.0 (38.2 to 46.2); Usual Care Control 43.5 (39.7 to 47.6)
• Physical Functioning (Secondary), Count of participants, Participants: ePRO Intervention 227; Usual Care Control 195
• Symptom Control (Secondary), Count of participants, Participants: ePRO Intervention 195; Usual Care Control 158
• Health-related Quality of Life (Secondary), Count of participants, Participants: ePRO Intervention 191; Usual Care Control 154
• Patient Satisfaction/Communication (Secondary), Number, participants: ePRO Intervention 480; Usual Care Control
• Emergency Department Utilization (Secondary), Count of participants, Participants: ePRO Intervention 315; Usual Care Control 273

Adverse events

Time frame: Participants were assessed for death for up to 2 years.

Limitations and caveats: This study was conducted during the pandemic when research and clinical resources at participating sites were strained with frequent turnover of staff. This disrupted accrual and conduct and likely decreased the effect size observed.

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• Results publication: Stover AM, Deal AM, Ginos B, Dueck A, Spears PA, Jansen J, Carr P, Henson S, Bennett AV, Jonsson M, Snyder C, Basch E. Impact of Providing an Automated Telephone Option to Report Weekly Patient-Reported Outcome Measures in the PRO-TECT Trial (AFT-39) on Disparity Gaps in Symptom Management and Outcomes. JCO Clin Cancer Inform. 2025 May;9:e2500046. doi: 10.1200/CCI-25-00046. Epub 2025 May 23. PMID 40408610
• Results publication: Mody GN, Bennett AV, Stover AM, Jonsson M, Teal R, Vu M, Carda-Auten J, Jansen J, Carr P, Dueck A, Henson S, Basch E. Implementation of Symptom Monitoring With Electronic Patient-Reported Outcomes: Perspectives and Recommendations From Community Oncology Practices (Alliance AFT-39). JCO Oncol Pract. 2025 Dec;21(12):1830-1837. doi: 10.1200/OP-24-00627. Epub 2025 Apr 11. PMID 40215451
• Results publication: Basch E, Schrag D, Jansen J, Henson S, Ginos B, Stover AM, Carr P, Spears PA, Jonsson M, Deal AM, Bennett AV, Thanarajasingam G, Rogak L, Reeve BB, Snyder C, Bruner D, Cella D, Kottschade LA, Perlmutter J, Geoghegan C, Given B, Mazza GL, Miller R, Strasser JF, Zylla DM, Weiss A, Blinder VS, Wolf AP, Dueck AC. Symptom monitoring with electronic patient-reported outcomes during cancer treatment: final results of the PRO-TECT cluster-randomized trial. Nat Med. 2025 Apr;31(4):1225-1232. doi: 10.1038/s41591-025-03507-y. Epub 2025 Feb 7. PMID 39920394
• Results publication: Lee MK, Mitchell SA, Basch E, Mazza GL, Langlais BT, Thanarajasingam G, Ginos BF, Rogak L, Meek EA, Jansen J, Deal AM, Carr P, Blinder VS, Jonsson M, Mody GN, Mendoza TR, Bennett AV, Schrag D, Dueck AC. Identification of meaningful individual-level change thresholds for worsening on the patient-reported outcomes version of the common terminology criteria for adverse events (PRO-CTCAE(R)). Qual Life Res. 2025 Feb;34(2):495-507. doi: 10.1007/s11136-024-03819-5. Epub 2024 Nov 6. PMID 39503942
• Results publication: Basch E, Schrag D, Henson S, Jansen J, Ginos B, Stover AM, Carr P, Spears PA, Jonsson M, Deal AM, Bennett AV, Thanarajasingam G, Rogak LJ, Reeve BB, Snyder C, Bruner D, Cella D, Kottschade LA, Perlmutter J, Geoghegan C, Samuel-Ryals CA, Given B, Mazza GL, Miller R, Strasser JF, Zylla DM, Weiss A, Blinder VS, Dueck AC. Effect of Electronic Symptom Monitoring on Patient-Reported Outcomes Among Patients With Metastatic Cancer: A Randomized Clinical Trial. JAMA. 2022 Jun 28;327(24):2413-2422. doi: 10.1001/jama.2022.9265. PMID 35661856
• Results publication: Basch E, Stover AM, Schrag D, Chung A, Jansen J, Henson S, Carr P, Ginos B, Deal A, Spears PA, Jonsson M, Bennett AV, Mody G, Thanarajasingam G, Rogak LJ, Reeve BB, Snyder C, Kottschade LA, Charlot M, Weiss A, Bruner D, Dueck AC. Clinical Utility and User Perceptions of a Digital System for Electronic Patient-Reported Symptom Monitoring During Routine Cancer Care: Findings From the PRO-TECT Trial. JCO Clin Cancer Inform. 2020 Oct;4:947-957. doi: 10.1200/CCI.20.00081. PMID 33112661

• Study Protocol (PDF, 2020-12-05)
• Statistical Analysis Plan (PDF, 2022-09-30)

• Ethan Basch, MD, Study chair, University of North Carolina, Chapel Hill