The Impact of Non-compliance to Standardized Risk-adjusted Protocol in Non-Muscle Invasive Bladder Cancer on Recurrence, Progression and Mortality: Lessons to Learn in the Era of COVID-19

Abstract

resection of bladder tumor (TURBT), cystoscopies and Intravesical therapy such as intravesical-Mitomycin (IV-MMC), and Bacillus Calmette-Guérin (BCG). European association of urology (EAU) strongly recommends following a risk strati cation approach in NMIBC regarding cystoscopy surveillance and Intravesical therapy which mainly depends on tumor size, focality, grade, presence of CIS, and recurrences [4]. Several studies published the natural history of NMIBC mainly in view of recurrence and progression which led to creating a scoring model by EAU to predict them based on the number of tumors, tumor diameter, prior recurrence, concurrent CIS, and pathological stage and grade [4,5].
There is strong evidence to support the importance of strict adherence to a surveillance protocol in NMIBC to decrease recurrence, progression, and improve cancer-speci c survival [4]. However, the literature is sparse regarding the effect of non-adherence to a standardized protocol or the outcome of delaying surveillance cystoscopies. For instance, during the current COVID-19 pandemic, several papers and guidelines recommend delaying NMIBC treatment and surveillance especially in the low-risk category, Albeit, this is based on scanty data but no level one evidence with no consensus about the impact of such delay on tumour recurrence and progression [6].
Therefore, the goal of this study is to identify the impact of non-adherence to standardized risk-adjusted surveillance and intravesical treatment on recurrence rate (RR), progression rate (PR), and mortality rate (MR) based on our experience in the developing countries as we don not have a regional guidelines and not all centres follow the international guidelines. It is hoped that this research will contribute to a deeper understanding of the adverse outcomes associated with non-compliance to a surveillance protocol in NMIBC. Also, this may in uence the decision of delaying treatment and surveillance of NMIBC in the era of the COVID-19 pandemic which may stay longer than previously expected [7].

Study design
It is a retrospective cohort study to evaluate the impact of non-compliance to standardized risk-adjusted surveillance and treatment in NMIBC. We have used the EAU risk strati cation and surveillance protocol as a reference which is widely accepted and used in most European centres as we don't have national guidelines [8].

Study Setting
The data was collected from two tertiary urology centres dealing with bladder cancer in Northern Palestine which cover a total population of 300,000.

Study population and sampling
We reviewed 20,000 histopathological reports in between 2012-2017. Two hundred bladder biopsies and resections reports were extracted Inclusion and exclusion criteria High risk: missing three or more.
Each group was studied and compared to others in order to relate them with adverse outcomes (RR over 3 years, PR over 3 years (Progression de ned as muscle invasion, prostatic stroma invasion, or development of regional lymphadenopathy on CT scan). In addition, the metastatic rate (MsR) and MR (Non-cancer-speci c) also were evaluated. The clinical and statistical signi cance is noticed between group 0 and group 2, thus we focused our research on both groups.

Statistical Analysis
All analysis was performed with IBM Statistical Package for Social Sciences program (SPSS) Statistics version 21.0. Categorical variables were presented as absolute frequency (percentage). The Pearson's Chisquare test or Fisher's exact test, as appropriate, was applied to assess the differences in categorical variables. P values < 0.05 were considered statistically signi cant. Kaplan-Meier (KM) techniques were used to generate mortality probabilities among adherent versus non-adherent patients in the follow-up of NMIBC with high-risk at each consecutive month until 5 years post-diagnosis. A scoring system is created to assess the effect of missing different variables during the surveillance of high-risk patients on RR, PR, and MR. The Scoring system composed of 4 items extracted from EAU surveillance protocol for the highrisk group as clari ed in Table 1. Table 1 Scoring System for high risk group.  (Table 2A).

Variables
Staging, grading and risk strati cation 66 (75%) had a lack of accurate pathological staging but vaguely described as papillary NMIBC. However, grading was accurately recorded where the majority (66, 75%) of the specimens were high grade (G2-3). 47% had muscle during the rst resection, Nevertheless, the rest of our cohort had con rmatory NMIBC diagnosis during re-resection during the rst 3 months of diagnosis.
The patients were distributed into three main risk group categories according to the EAU risk strati cation [8]. The largest group was the high-risk group which contains 63 patients (71.5%), while the low and intermediate group entails 25 patients (28.5%); (Table 2B).
General compliance to surveillance cystoscopy, RR, PR, MsR, and MR.
Generally, most of the cohort are not compliant to the surveillance cystoscopy protocol as just 20 (23%) patients were compliant. More than 80% had recurrence tumors over the 3 years follow up. Progression was noticed in 34 (38.6%) but 8 (9%) had no data available about progression. The MR is around 18% (Table 2C).  (P < 0.001), MsR: (37.7%) (P < 0.001), MR: (23.5%) (P = 0.002) respectively. Obviously, patients older than 60 years old is less compliant to surveillance cystoscopy protocol 56 (82%) (P = 0.001); (Table 3). Risk group sub-analysis (Compliance and relation to RR, PR and MR) The major statistical signi cant is seen when you compare Group 0 (compliant) to group 2 (Noncompliant 2) as for instance, in the intermediate rate and high-risk group, the PR rate in the compliant group is none while it is 100% (P < 0.001) and 56.4% (P = 0.001) in the non-compliant group respectively (Table 4). Furthermore, the MR is statically signi cantly higher in the high-risk group 25% (P = 0.03) which mandates us to evaluate the mortality rate over 5 years using KM curve.

KM curve
Forty-ve patients were diagnosed with NMIBC between January 2012 and May 2015. Among these patients, 7 were compliant and 38 were non-compliant. We followed them up until May 2020. 15 deaths were found and all of them were non-compliant. To conclude, KM graph shows that compliant patients were more likely to be better than non-compliant. This nding did not reach statistical signi cance (P = 0.075) because all died patients were non-compliant (Fig. 1).
Scoring system to predict recurrence, progression, and mortality in high-risk patients with poor compliance A scoring system has been created to assess the effect of missing different variables during the surveillance of high-risk patients on RR, PR, and MR. Thirty-six patients from the high-risk group were assessed regarding the compliance to EAU high-risk surveillance protocol mainly procedures and treatments which is proven to have an impact of recurrence, progression, and mortality. Therefore, we assess the statistically signi cant of having a score three or more in relation to RR, PR and MR. Scoring three or more is statistically and clinically signi cant associated with higher recurrence, progression, and mortality. RR: (94%) (P = 0.016), PR: 49% (P < 0.001) and MR (26%) (P = 0.012); (Table 5).

Discussion
Our study has been performed during this period of a worldwide COVID-19 pandemic negatively affecting the health system and led to a signi cant burden on hospitals and daycare units [7]. We have evaluated the outcomes of non -compliance to surveillance protocol in the management of NMIBC to further understand the natural history of this disease and outcomes of delaying surveillance cystoscopies as it is currently suggested by several published articles [6]. Obviously, our data shows that the PR and RR are signi cantly higher in the non-compliant group which highlights the importance of following a validated surveillance protocol and not delaying surveillance cystoscopies or missing intravesical treatment despite the current challenges facing the health system globally during the COVID-19 pandemic mainly in the high-risk group.
NMIBC diagnosis and management algorithm is well established where various international protocols and guidelines are available. For instance, EAU annually updates the guidance on NMIBC surveillance and management, in addition to creating a scoring model to predict progression and recurrence which are the most important factors in NMIBC prognosis [8].
However, in Palestine and other regions in the Middle East, there is no local guidance to manage NMIBC which makes expert opinion and international guidelines are both the mainstay way of diagnosis and management. Furthermore, patient compliance is an issue for several reasons such as nancial problems, false beliefs, and more recently the current COVID-19 pandemic. Therefore, we have used this deviation from the standard of care to answer the compelling question in the literature about how strict we should be following surveillance cystoscopies and other treatments in NMIBC management.
Few articles recently raised a question regarding the impact of overuse cystoscopy in low-risk NMIBC on cost and hospital occupancy, on the contrary, underuse in high risk may be associated with serious adverse outcomes. Therefore, a huge debate has been raised recently regarding the strict adherence to surveillance cystoscopies taking into account that NMIBC disease is a wide spectrum disease ranging from low risk to high risk with no available current data regarding the impact of noncompliance to a standardized risk-adjusted protocol on recurrence, progression and mortality [9,10]. Furthermore, several papers currently have been published to safely organize urology work during the COVID-19 pandemic which includes the suggestion of delaying NMIBC surveillance and treatment [6]. This evolving concept may harbor hidden harm if not well studied mainly in the high-risk group which is the group most commonly associated with recurrence and progression according to the EAU scoring prediction model and also it is the most prevalent in our study (71.5%) [8,9]. Furthermore, there is no available data to look comprehensively into the effect of non-compliance to the bladder cancer diagnosis and management pathway especially in the high-risk group which also includes the time of diagnosis, imaging, cytology, and intravesical therapy. Our data shows that the non-compliant NMIBC group has got higher RR, PR and MR. This outcome supports the importance of adherence to surveillance protocols regardless to the stage but more importantly in the high-risk group as our data shows that the PR rate in the compliant group is none while it is 100% (P ≤ .001) in non-compliant intermediate group and 56.4% (P = .001) in noncompliant high-risk group. Thus, NMIBC management especially high-risk category should be prioritized during the current COVID-19 pandemic and should not be delayed.
National Institute for health and care excellence guidelines (NICE guidelines) recommend a two-week wait pathway to diagnose bladder cancer especially if haematuria is the main presentation [10]. Our results showed that half of the patients had a delay in diagnosis despite having haematuria as the most prevalent presentation in our cohort which may also contribute to the overall bad prognosis. Furthermore, at the time of the rst resection 90% failed to have IV-MMC which may explain the high RR in all subgroups as single, immediate post-operative IV-MMC signi cantly reduces the RR compared to TURBT alone [11]. It is obvious that missing more items during NMIBC management is associated with the poorer outcome as our scoring model shows that scoring three or more is signi cantly associated with higher recurrence, progression and mortality. This can be used in regions where compliance to surveillance protocol is an issue to counsel patients about the negative impact on poor compliance on recurrence, progression and mortality. KM curve shows that compliant patients were more likely to do better than the non-compliant group over 5 years follow up The high-risk group carries the highest risk of progression. Therefore, this category has been thoroughly evaluated in order to decrease the risk of progression which affects overall prognosis. Several strategies have been recommended to treat this group such as full-dose intravesical BCG for one to three years, creation a subgroup of highest risk tumours by EAU and upfront cystectomy in some cases [4,12,13]. In our article, the group 2 non-compliant high-risk group is associated with a signi cant PR and quarter MR. Thus, adherence to a surveillance protocol in the high-risk group is strongly recommended and should be followed strictly. More importantly, this will help to answer the trending question in the literature regarding the importance of surveillance cystoscopies during the COVID-19 pandemic which negatively affects health economic, medical personal, and hospital occupancy [14].

Limitations Of The Study
This study has got few limitations such as a small sample size, few patients lost to follow up, or had some data not available, and lack of standardization of pathology reports. This might have led to missing the primary diagnosis of NMIBC initially in a few cases which may explain the higher MsR and MR. However, this study represents the outcome of deviation from the standard of care and help to clarify the impact of it on prognosis and associated adverse outcomes especially in the high-risk group.

Conclusions
NMIBC is a potentially controllable disease with an excellent outcome if surveillance protocol is applied and followed. However, this study shows that the noncompliance group has a signi cantly worse outcome in comparison to the compliant group. RR, PR, and MR are higher in the non-compliance group. Thus, strict adherence to international guidelines is strongly recommended especially in the high-risk group and NMIBC management should be prioritized in the era of the COVID-19 pandemic.  Figure 1