Correlation Between Electronic Patient-Reported Outcomes and Biological Markers of Key Parameters in Acute Radiation Cystitis Among Patients With Prostate Cancer (RABBIO): Prospective Observational Study

Abstract

Background: Despite advances in radiation techniques, radiation cystitis (RC) remains a significant cause of morbidity from pelvic radiotherapy, which may affect patients' quality of life (QoL). The pathophysiology of RC is not well understood, which limits the development of effective treatments.

Objective: The Radiotoxicity Bladder Biomarkers study aims to investigate the correlation between blood and urinary biomarkers and the intensity of acute RC symptoms and QoL in patients undergoing localized prostate cancer radiotherapy.

Methods: This study included patients with low- or intermediate-risk localized prostate cancer who were eligible for localized radiotherapy. Blood and urinary biomarkers were analyzed before radiotherapy was initiated and at weeks 4 and 12 of radiation therapy. Patients completed questionnaires related to RC symptoms and QoL (International Prostate Symptom Score and Functional Assessment of Cancer Therapy-Prostate [FACT-P]) using a digital remote monitoring platform. The information was processed by means of an algorithm, which classified patients according to the severity of symptoms and adverse events reported. Levels of blood and urinary biomarkers were tested with the severity of acute RC symptoms and patient-reported QoL.

Results: A total of 401 adverse events questionnaires were collected over the duration of this study from 20 patients. The most frequently reported adverse events at week 4 were pollakiuria, constipation, and diarrhea. In comparison with baseline, the mean FACT-P score decreased at week 4. A significant increase in the proportion of M2 phenotype cells (CD206+, CD163+, CD204+) at W12 compared to W0 was observed. An increase in serum and urine levels of macrophage colony-stimulating factor (M-CSF), hepatocyte growth factor, and macrophagic inflammatory protein was observed at week 12 compared to baseline levels. Baseline serum and urine M-CSF concentrations showed a significant negative correlation with FACT-P scores at weeks 4 and 12 (r=-0.65, P=.04, and r=-0.76, P=.02, respectively).

Conclusions: The Radiotoxicity Bladder Biomarkers study is the first to explore the overexpression of inflammatory proteins in blood and urine of patients with symptoms of acute RC. These preliminary findings suggest that serum and urine levels of hepatocyte growth factor, M-CSF, and macrophagic inflammatory protein, as well as macrophage polarization, are mobilized after prostate radiotherapy. The elevated M-CSF levels in serum and urine at baseline were associated with the deterioration of QoL during radiotherapy. The results of this study may help to develop mitigation strategies to limit radiation damage to the bladder.

Keywords: acute radiation cystitis; biomarkers; e-PRO; electronic patient-reported outcome; prostate cancer; quality of life.

Figure 1.. The RABBIO study design. RABBIO: Radiotoxicity Bladder Biomarkers.

Figure 2.. (A) Adverse events W0 to W12. (B) Clinical classifications W0 to W12. The clinical classifications were determined by the software medical device Cureety TechCare (scoring from the combination of adverse events). W: week.

Figure 3.. Timelines for each patient during irradiation: each line represents the monitoring of a patient and shows the clinical classifications computed by the device algorithm (green, yellow, orange, or red) from the completed questionnaires (black dots). The end of each timeline corresponds to the end of this study’s analysis.

Figure 4.. Quality of life measured via the FACT-P score. FACT-P: Functional Assessment of Cancer Therapy-Prostate.

Figure 5.. Analysis of the circulating immune cell population by flow cytometry. (A) Representative FACS dot plots to identify macrophage M2a (CD86+ CD163+) and M2c (CD163+ CD206+). (B) Increased ratio of macrophage phenotype M2 (macrophage M2a [CD86+ CD163+] and M2c [CD163+ CD206+]). Mann Whitney test: ratio versus W0 (before radiotherapy), *P<.05, **P<.01, ns. FACS: flow cytometry; ns: not significant; W: week.

Figure 6.. Changes in serum cytokine levels. Mann Whitney test: ratio versus W0 (before radiotherapy), *P<.05, **P<.01, ns. HGF: hepatocyte growth factor; M-CSF: macrophage colony-stimulating factor; ns: not significant; W: week.

Figure 7.. Changes in urine cytokine levels. Mann Whitney test: ratio versus W0 (before radiotherapy), *P<.05, **P<.01, ns. HGF: hepatocyte growth factor; MIP: macrophagic inflammatory protein; ns: not significant; W: week.

Figure 8.. Correlation matrices between FACT-P scores and cytokine concentrations in serum (A) and urine (B). Empty cells indicate a nonsignificant correlation (P>.05). When significant (P<.05), numbers correspond to r correlation coefficients, positive or negative (Pearson test). FACT-P: Functional Assessment of Cancer Therapy-Prostate.