Patient-Reported Outcome Measures compared to Clinician Reported Outcomes regarding incontinence and erectile dysfunction in localized prostate carcinoma after Robot Assisted Radical Prostatectomy: impact on management

Purpose/ Background: To examine whether a discrepancy between patient reported outcomes (PROs) and clinician reported outcomes (CROs) impacts the management of urinary incontinence (UI) and erectile dysfunction (ED) after robot assisted radical prostatectomy (RARP). Methods: Up to 1 year after RARP, UI and ED recovery of 312 men with localized and locally advanced prostate cancer were assessed using the International Consultation Incontinence Questionnaire Short Form (ICIQ-SF) and the International Index of Erectile Function (IIEF-EF) and CROs by interview. Discrepancies between PROs and CROs were studied in light of treatment offered and management. Results: The ICIQ-SF Score matched with CROs in all sum score categories except in ICIQ sum score 6-12; here the UI was underreported by clinicians in 58% and 59% of patients at 8 and 12 months (p<.001). Furthermore, at 8 and 12 months postoperatively, clinicians underreported UI in 29% and 23% of patients with ICIQ score 13-18 (p<.001). The clinician signi�cantly over-reported the recovery of erectile function (“normal erection”) (p<.001), especially in men with IIEF-EF sum score 6-16. Independently of ICIQ-SF/IIEF-EF scores, discrepancy between PROs and CROs did not affect rate of health care offered to patients. Conclusions: This is to our knowledge the �rst study that compared the PROs with clinician reported functional outcomes and the impact of discrepancies on the management of side effects of RARP in prostate cancer. Observed discrepancies between the PROs and CROs did not affect offered management and counseling of UI and ED.


Introduction
Robot-Assisted Radical Prostatectomy (RARP) is one of the treatment options for patients with localized prostate cancer. 1 The most bothersome side effects of RARP are urinary incontinence (UI) and erectile dysfunction (ED). 2 Identi cation of cancer recurrence and side effect monitoring by clinicians are the basis for prostate cancer follow-up care. Clinicians acknowledge that the use of PROMs in clinical practice is useful for FU after treatment of prostate cancer but the results of the PROMs are rarely taken into account during the consultation with the clinician. 7[6][7][8][9][10] The primary aim of this study was to compare PROs and Clinician Reported Outcomes (CROs) concerning urinary continence and erectile function after RARP.Secondarily, we hypothesized that clinicians would underestimate UI and ED compared to PROs and that this may impact the management of UI and ED, which could potentially lead to undertreatment of these common side effects.

Study population
Between August 2016 and January 2020, men were prospectively enrolled in a cohort study at the Netherlands Cancer Institute (NCI).All men had a localized or locally advanced prostate cancer and underwent primary or salvage RARP with or without lymph node dissection.Only patients with at least 1 year FU and available PROs and CROs were included.The institutional review board of the NCI approved the study (IRBd20-368).

Data
The following data were collected from the institutional database: age at the time of rst consultation, body mass index (BMI), pre-operative prostate-speci c membrane antigen (PSA) level, clinical tumor (cT) stage, pathological tumor (pT) stage, pathological nodal (pN) stage, postoperative Gleason score, preoperative comorbidity status as assessed by the Charlson index, and marital status.The patient les were evaluated for clinicians' advice on additional treatment (medication / physiotherapy) for UI and ED.

Outcome assessment
The primary outcome was to compare the PROs with CROs.

PROs:
We sent questionnaires to patients preoperatively, at 6 and 12 months after RARP.The PRO assessment of recovery of continence was done with the International Consultation on Incontinence Questionnaire -Urinary Incontinence Short form (ICIQ-SF) in order to evaluate the severity of urinary incontinence. 11The answers from ICIQ-SF resulted in a sum score, with a minimum score of 0, and a maximum score of 21.

CROs:
CROs were obtained during the 8 and 12 months postoperative consultations.The clinician prescribed medicine or referred patients to manage postoperative symptoms.CROs obtained at 8 and 12 months were compared with PROs at 6 and 12 months postoperatively, respectively.
During FU visits the patients were asked if they had any involuntary loss of urine.The answer was noted as: "continence", "drops", "use of 1 diaper a day" or "use of more than 1 diaper a day".At the time of consultation with the clinician, the patient was interviewed about the status of EF.The answer was noted as: "normal EF", "weak EF", "no EF", use of phosphodiesterase type 5 inhibitor (PDE-5i)", "use of intracavernosal injection (ICI)".The clinician proposed help for UI and ED and it was de ned as: "help not needed by patients", "referring/prescription".When the clinician did not proposed help, it was noted as: "help not offered by clinician".The extent of per-operative nerve sparing was obtained using the Fascia Preservation (FP) Score 13 and ranged from 0 to 12.

Statistics
Data were summarized by frequency and percentage for categorical variables and mean (standard deviation) for continuous variables.
Descriptive analysis was performed for CROs collected at 8 and 12 months postoperative and for PROs at 6 and 12 months postoperative.
CROs and PROs about side effects of RARP were correlated with medical treatment or referral for sexual counseling/pelvic oor exercises proposed (or not) by clinician.
Data of the clinician reports were dichotomized for urinary continence (continence/drops versus incontinence (use of layers)) and for erectile function (erection=normal erection/and weak erection versus erectile dysfunction=no erection, use of PDE-5i or ICI).
We analyzed the discrepancy between PROs and CROs by dividing patients in agreement and disagreement groups.Agreement for continence/incontinence was de ned as ICIQ-SF 0-5 and continence to use of 1 safety pad or ICIQ-SF 6-21 and use of 1 or more pads, while disagreement was de ned as ICIQ 0-5 and use of 1 or more pads / ICIQ 6-21 and 0-1 safety pad.Agreement for erection/ED was de ned as IIEF-EF 17-30 and erection or IIEF-EF 0-16 and ED, while disagreement was de ned as IIEF-EF 17-30 and ED/ IIEF-EF 1-16 and erection.
All statistical tests were two-sided, and discrepancies were considered statistically signi cant with pvalues ≤ 0.05.Statistical analysis was carried out with IBM SPSS Statistics V27.0 (SPSS INC., Chicago, Ill).

Discussion
Our study is the rst to demonstrate the impact of discrepancy between PROs and CROs on the management of incontinence and ED after RARP.The discrepancy between the PROs and the CROs with regard to UI mainly concerned patients with mild and moderate urinary incontinence and did not lead to a signi cant difference in the treatments offered.All men reporting severe urinary incontinence postoperatively were identi ed by clinician report.This nding con rmed that the discrepancy between PRO and CRO did not impact treatment/help proposed for UI.Similarly, EF reported by PROMS was mirrored by clinician reporting and the majority of men were offered penile rehabilitation.In our study, outpatient consultation after RARP focused on identi cation of cancer recurrence (PSA), UI, and ED outcomes.A previous study has shown that patient-centered communication can improve urinary symptoms after RARP through better symptom management. 14It seems that patients in our study did receive treatment of UI or ED when needed, despite the discrepancy between PROs and CROs as clinicians focused in their communication on patient centered outcomes.
Basch et al. 15 compared symptoms due to treatment toxicity of chemotherapy between patients and clinicians using the Common Terminology Criteria for Adverse Events (CTCAE) and showed that the discrepancy in reporting of symptom severity related to subjective symptoms such as nausea and fatigue rarely in uenced treatment decisions.Although we did not use the CTCAE to assess symptoms, our study con rmed these results as the discrepancy between PROs and CROs did not affect offered management and counseling of UI and ED.However, clinicians did not always ask for EF and did not always offer help for ED, especially at 4 months postoperatively (in 28% of patients).This result is surprising because we know that early penile rehabilitation after RARP is recommended in patients with preoperative normal EF. 16 this study, we demonstrated the discrepancy between the PROs and CROs regarding the urinary continence and EF after RARP.The discrepancy between PROs and CROs in cancer patients care is well known and was previously demonstrated in literature. 17Rammant et al. 18 described the discrepancy between PROs and CROs by using the CTCAE in prostate cancer treatment (external beam radiotherapy).
A signi cant disagreement in UI (under-reportage of clinician) was found at all post treatment time points (95%CI 0.19 to 0.55; 0.39 to 0.69 and 0.21 to 0.55).Our analysis con rmed these results: incontinence was underreported by clinicians compared to the PROs especially in patients with moderate incontinence (ICIQ-SF score 6-12).This could be explained by the di culty for clinicians to interpret the loss of urinary drops.Patients often report sporadic loss of urine droplets and clinicians may subjectively interpret this as continence.Basch et al. 15 demonstrated that the severity of urinary frequency was under-graded by clinicians.Compared to our ndings, these results con rm that subjective genitourinary symptoms are di cult to interpret by clinicians.Severe UI (ICIQ-SF score 13-18) was also underreported by clinicians at 8 and 12 months post RARP.This is surprising because severe UI is very different in severity compared to loss of urinary droplets.Thus, we did not expect underreporting by clinicians with regard to severe UI, especially since a strong correlation was shown between the use of pads (> 1 pads daily) and the ICIQ-SF score 19-21, which demonstrated that very severe incontinence was correctly reported by clinicians.Gori et al. 19 noted moderate agreement in UI after prostatectomy between the PROM (EPIC-26) and the clinical reports and developed a tool to prevent measurement bias.This tool correlated a number of questions from the EPIC-26 with incontinence versus continence.In our study, we used the ICIQ-SF as PROM.We compared UI and continence (with the use of pads or not) with the results of the ICIQ-Score.Therefore, a tool should be developed to avoid biased measurement between ICIQ-SF and CRO by using the model of Gori et al. and by classifying the answers to question 1 of ICIQ-SF ("how often do you leak urine?") in continence ("never", "about once a week or less often") and incontinence ("2 or 3 times a week", "about once a day", "several times a day", "all the time").Also, to minimize and avoid the misinterpretation in moderate UI, it could be helpful to use the PROs initially during the consultation and discuss the outcomes with the patients.Moreover, when PROMs are used by clinicians during the consultation, it could improve patient-centered communication. 14rprisingly, clinicians signi cantly overestimated the recovery of EF (normal erection) in patients with IIEF-EF score 6-16.This discrepancy is di cult to explain.The difference might lie in the subjectivity of interpretation by the clinician of a normal EF or/and on the information given by patient.It also might be di cult for patients to report ED to the clinician.Chambers et al. showed that it could give them a negative image of their masculinity. 20 this study, IIEF-EF score between 17-21 was considered as normal EF.However, there is no agreement in the literature about the optimal cutoff for normal EF in IIEF-EF score. 21It is interesting to notice that the clinician did not report normal EF 1 year after RARP in patients with IIEF-EF score between 17-21.This nding is probably due to the cutoff we have de ned for normal EF (≥ 17).The results could have been different with a different cutoff IIEF-EF score.
In this study we compared the PROs with the CROs concerning the urinary continence and EF after RARP.The differences between the PROs and the CROs did not affect the treatment of these symptoms.However, it is incorrect to conclude that PROMs are not needed in clinical practice since some side effects clearly seemed underestimated.The PROMs also include other items which are primordial for the QoL of patients.According cancer survivors, clinicians do not have a good knowledge of QoL of their patients. 22he implementation of the PROs in electronic health records could help the clinician to focus on all patient-centered needs.
Limitations the retrospective nature of treatment analysis is the main limitation of the presented data.CROs were retrospectively explored in medical les.It is possible that the clinician asked about side effects but did not report the nding in the medical le.Furthermore, this study was focused only on two side effects of RARP (UI and ED) which status can be subjectively interpreted by clinicians.These results do not fully re ect the importance of using PROMs during the consultation, as PROMs evaluate many other aspect of QOL.

Conclusion
This study is, to our knowledge, the rst study to compare PROs with CROs analyzing the impact of discrepancies on management of UI and ED after RARP.

Table 1
Patients characteristics (n = 312) CROs were available in all patients at 12 months.Clinician did not ask for continence status and for EF in 3% (n = 10/312) and 10% (n = 32/312) of patients respectively.Clinicians reported urinary continence/ loss of urinary droplets in 80% (n = 243/302) of patients and use of ≥ 1 pads daily in 19% (n = 57/302).), the CRO was in agreement.Discrepancies between PRO and CRO were mainly observed in patients in the intermediate categories of ICIQ-SF 6-12 and 13-18 scores.In those categories, the CRO appeared to vary from no pad to > 1 pads.

Table 2a (
dis)agreement urinary continence PROs versus CROs and help proposed *PRO at 6 months and CROs at 8 months.Abbreviations: RARP: Robot Assisted Radical Prostatectomy.PRO: Patient Reported Outcomes.CRO: Clinician Reported Outcomes.EF: Erectile Function.ED: Erectile Dysfunction.IIEF-EF: International Index of Erectile Function-Erectile Function domain 2.5.2 (Dis)agreement and symptoms management at 12 months (PROs and CROs) postoperatively majority of patients with IIEF-EF score 1-16 at 12 months (87%, n = 103/118) refused help.In total 13% (n = 40/312) of patients indicated they already had a treatment for ED.From these patients 77% (31/40) had IIEF-EF score < 17 with a majority of IIEF-EF score 6-10 (45%; n = 18/40) and 12% (n = 5/40) had IIEF-EF Score > 24.Agreement and disagreement between IIEF-EF and help proposed, received or declined is described in Table The clinician underreported moderate and severe incontinence and over-reported the recovery of EF (normal erection) in patients with IIEF-EF score 6-16 Regardless of discrepancies in PROs and CROs, patients received clinician help for UI and ED.Netherlands Cancer Institute; BMI: Body Mass Index; PSA: prostate-speci c membrane antigen; ICIQ-SF: Incontinence Questionnaire -Urinary Incontinence Short Form; EF: Erectile Function; IIEF : International Index of Erectile Function; IIEF-EF: Erectile Function domain of the International Index of Erectile Function; PDE-5i: Phosphodiesterase type 5 inhibitor; ICI: Intracavernosal Tillier CN: no con ict of interest or competing interest Boekhout AH: no con ict of interest or competing interest Veerman H: no con ict of interest or competing interest Wollersheim BM: no con ict of interest or competing interest Groen PAM: no con ict of interest or competing interest van der Poel HG: no con ict of interest or competing interest van de Poll-Franse LV: no con ict of interest or competing interest Authors' contributions: