Evaluating a novel technology in radiotherapy using digital patient-reported outcomes: The PRO-MR-RT study

Background
In 2018, patients with cancer could be treated with online adaptive magnetic resonance-guided radiotherapy. The magnetic resonance linear accelerator (MR-linac) is an innovative technology that combines high-quality MR-images with a linear accelerator for cancer treatment and online plan adaption. The MR-linac visualises the tumour and surrounding organs during treatment, making it possible to adapt the radiotherapy plan to the anatomy of the day. Consequent-ly, safety margins around the tumour can be reduced and doses escalated. Especially tumours in the pelvic area are better visualised on high-quality MRI, thus treated at the MR-linac.

Since the toxicity profiles of the patients may change, it is important to evaluate the adverse events (AEs) of this new technology timely and accurately. Weekly toxicity assessment with patient-reported outcomes (PROs) could be valuable, as PROs in prior studies have captured symptoms earlier and with higher sever-ity than clinician toxicity reports. A weekly frequency would request a short, specific questionnaire capturing the most common acute AEs and an integration of PROs into a Danish radiotherapy setting.

This thesis is based on four papers aiming:

• To identify, select and validate a set of symptomatic AEs and correspond-ing PRO items covering the most common acute AEs among patients re-ceiving pelvic radiotherapy (PAPER I).

• To explore the feasibility, usability, and patient acceptance of weekly elec-tronic PRO assessments during and four weeks following radiotherapy and for six months of follow-up (PAPER II).

• To investigate the acute AE trajectories, time to maximum worsening of symptoms, and the persistence of symptoms among patients with prostate cancer (PCa) treated at the MR-linac (MANUSCRIPT III).

• To explore the clinical impact of PRO integration with real-time symptom monitoring in radiotherapy and patient follow-up selection based on their reported health. Furthermore, to investigate if clinician compliance in acting on PROs is associated with patient response rates and patients experienc-ing their PROs being used for their care (MANUSCRIPT IV).

Results
• In a literature review and chart audit with MR linac patients, 18 acute symptomatic AEs were identified, and the corresponding PRO items were selected in two validated item libraries. In a pilot study, the content of the pelvic PRO item set was validated (n=40), and 17 acute AEs had a preva-lence >20%, thus useful for capturing acute AEs in pelvic radiotherapy.

• It was feasible to recruit (87%) and adhere patients with cervical or pros-tate cancer to weekly PROs during radiotherapy. The length and weekly frequency of the pelvic PRO item set were acceptable, and 85% respond-ed to more than 80% of the weekly PROs, thus a lower adherence above age 70 (p=0.041). The response rate declined during follow-up, with a re-tention rate of 47.5% in week 24. The application was usable for digital PRO completion; however, the patients requested real-time clinician feed-back.

• For patients with intermediate-risk PCa (n=25) or low-volume metastatic PCa (n=25) treated at the MR-linac, the weekly PROs comprised detailed toxicity profiles. Overall, 20% reported a two-level increase in urinary fre-quency over two consecutive weeks. Symptoms peaked outside the time points used in prior studies (60 Gy, week 3, 36 Gy, follow-up week 1-2). Urinary symptoms (16%) persisted for more than 12 weeks for patients treated with 20 fractions, while the persistence of bowel symptoms (12%) was more profound in the short courses with six fractions.

• The integration of active real-time monitoring of PROs in radiotherapy for PCa (n=156) improved the patient experience of quality of care (87%), communication (91%) and feeling of being involved (93%). The clinician handled all PROs for most patients (93%), and the patients found PROs were used for their care (95%). Follow-up on acute AEs was deselected by 23%. A higher percentage of these patients (68%) reported deteriorated self-rated health two months following as opposed to those choosing fol-low-up (40%).

Conclusion
A short PRO item set was developed and validated for pelvic cancer patients and integrated into a clinical radiotherapy setting. A pilot study confirmed the feasibility, usability and acceptance of weekly PRO completion. For patients with PCa treated at the MR-Linac, the weekly PROs comprised acute AE trajec-tories with real-time improved or deteriorated symptoms. Active digital monitor-ing of PROs was integrated for all patients with PCa, resulting in high clinician and patient compliance. Patients experienced their PROs were used and im-proved their care and one-forth deselected follow-up.