Bladder cancer prospective cohort study on high-risk non-muscle invasive bladder cancer after photodynamic diagnosis-assisted transurethral resection of the bladder tumor (BRIGHT study)

Introduction

Bladder cancer is associated with very high morbidity and mortality rates, with 430 000 new cases and 1.65 million deaths worldwide every year.¹ The standard therapy for NMIBC, which accounts for approximately 70% of bladder cancers, is TURBT.² TURBT is performed for complete tumor resection. However, patients with high-risk NMIBC, defined as pT1 cancer invading the lamina propria, high-grade UC, or CIS, show residual tumor detection rates of 33–78% during the second TURBT,^{3, 4} with the majority of residual tumors appearing in the first TURBT lesion area.⁴ Therefore, a second TURBT is strongly recommended 3–8 weeks after the first procedure.^{2, 5, 6}

PDD involves the administration of the photosensitizers 5-ALA and HAL in either an oral (5-ALA) or intravesical (5-ALA, HAL) manner. PPIX is also administered, which selectively accumulates in tumor cells and is excited by blue light (400–410 nm) using a fluorescent cystoscope, and lesions that show red fluorescence (approximately 635 nm) are detected. PDD can improve the detection rate of CIS,^{7, 8} and TURBT combined with PDD (PDD-TURBT) can reduce the residual tumor and intravesical recurrence rates.^9-11 The residual tumor rate in patients treated with PDD-TURBT, including high-risk cases, was 10.3%, which was significantly lower than that associated with normal TUR (25.4%).¹² However, the residual rate for high-risk cases defined according to the 8th edition of the Union of International Cancer Control has not been reported. In Japan, treatment with oral 5-ALA hydrochloride has been covered by health insurance since 2017, and PDD-TURBT is now included in the list of insured medical treatments.^13-15

This study aimed to compare the residual tumor rate after initial PDD-TURBT for high-risk cases with those after the second TURBT for high-risk NMIBC cases previously treated with WL. We also investigated the usefulness of PDD-TURBT and created a risk-stratification model to identify cases that may not require a second TURBT. To our knowledge, this is the first multicenter prospective study to investigate the residual tumor rate after PDD-TURBT using oral 5-ALA hydrochloride for high-risk NMIBC cases to our knowledge (UMIN ID: UMIN000035712).

Methods

Results

Summary of the study

Among the 188 cases registered in the PDD group, 177 were included in the analyses after excluding 11 ineligible cases. For historical data evaluation, 306 of the 313 cases registered in the WL group were analyzed after excluding seven ineligible cases (Fig. 1). The patient backgrounds of each group are shown in Table S1. Multivariate analysis using logistic regression was performed for the factors predicting residual tumors at the second TURBT in all 483 cases. Significant predictive factors included the presence of PDD use during the initial TURBT (P < 0.001; OR 0.46 [0.3–0.71]), number of tumors (P < 0.001; OR 2.58 [1.66–4.0]), and the presence of concurrent CIS during the initial TURBT (P = 0.003; OR 1.96 [1.24–3.11]) (Table S2).

Propensity score-matching analysis

The two groups were compared after propensity score matching (167 cases in each group). The two groups showed no significant differences in clinical background factors (Table 1). The residual tumor rates at the second TURBT, which was the primary endpoint, were 25.7% in the PDD group and 47.3% in the WL group, indicating significant differences between the two groups (P < 0.001; OR 0.39 [0.24–0.63]; Fig. 2). Upstaging to muscle-invasive bladder cancer at the second TURBT was observed in four cases (3.0%) in the WL group but not in the PDD group (data not shown).

Table 1. Patient characteristics of WL group and PDD group after propensity score-match analysis

	WL (%)	PDD (%)	P-value†
	(n = 167)	(n = 167)
Median age (interquartile range)	72 (64, 77)	72 (66, 77)	0.789
Sex
Female	25 (15.0)	24 (14.4)	1
Male	142 (85.0)	143 (85.6)
Previous NMIBC
No	152 (91.0)	152 (91.0)	1
Yes	15 (9.0)	15 (9.0)
History of UTUC
No	130 (77.8)	124 (74.3)	0.818
Yes	37 (22.2)	43 (25.7)
Tumor size
<3 cm	61 (36.5)	58 (34.7)	0.522
≥3 cm	106 (63.5)	109 (65.3)
Number of tumors
Single	157 (94.6)	156 (93.4)	0.819
Multiple	9 (5.4)	11 (6.6)
Residual tumor
Absence	88 (52.7)	124 (74.3)	<0.001
Presence	79 (47.3)	43 (25.7)

• † Statistical test performed: Fisher's exact test.

Prediction of residual tumor rate at the second TURBT after PDD-TURBT

Multivariate analysis using logistic regression was performed for the factors predicting residual tumors at the second TURBT after PDD-TURBT, using the data for the PDD group (177 cases) as participants. The significant predictive factors included the presence or absence of smoking (P = 0.034; OR 3.88 [1.11–13.6]), number of tumors (P = 0.042; OR 2.52 [1.04–6.13]), and pathological stage (P = 0.036; OR 2.52 [1.06–5.98]) (Table 2). The residual tumor rates at the second TURBT within the PDD group for each factor are shown in Table S3. In stratification, using the risk scores based on current/past smoking history, multiple tumors, and pTis/pT1 were set as 1, with the OR for the residual tumor risk of each variable. The residual tumor rates were 8.3% for cases with a risk score of 1 or less (n = 48) and 33.3% for those with a risk score of 2 or more (n = 129), and significant differences were found between the two groups (P < 0.001; OR 5.46 [1.81–22.28]; Fig. 3).

Table 2. Multivariable logistic regression analysis for residual tumor at second TUR in PDD group (n = 177)

	OR	95% CI	P-value
Age	0.98	0.94–1.03	0.578
Sex
Female versus male	0.76	0.23–2.55	0.664
Smoking status
No smoking versus past smoking	1.96	0.74–5.24	0.177
No smoking versus current smoking	3.88	1.11–13.6	0.034
ECOG performance status
0 versus 1	0.45	0.05–4.58	0.504
Previous NMIBC
No versus yes	1.03	0.34–3.11	0.957
History of UTUC
No versus yes	0.90	0.21–3.91	0.889
Tumor size
<3 cm versus ≥3 cm	1.30	0.58–2.94	0.528
Number of tumors
Single versus multiple	2.52	1.04–6.13	0.042
Concurrent CIS
No versus yes	1.29	0.54–3.09	0.564
Pathological stage
pTa versus pTis	5.67	0.29–113	0.255
pTa versus pT1	2.52	1.06–5.98	0.036
Tumor grade
Low versus high	0.62	0.09–4.06	0.616

Discussion

The present prospective study showed that an initial PDD-TURBT using oral 5-ALA hydrochloride for high-risk NMIBC could significantly reduce the residual tumor rate compared to conventional WL-TURBT. Smoking history, the number of tumors, and pathological stage were also identified as factors that influenced the occurrence of residual tumors at the second TURBT, in 48 cases (27%) with a risk score ≤1, calculated based on these factors, the residual tumor rate was <10%. Thus, the risk score model proposed in this study could be used to omit the second TURBT in approximately one-fourth of high-risk NMIBC cases.

A previous PDD-TURBT prospective trial using 5-ALA showed that the residual tumor rate in the PDD group was 4.5–32.7%, whereas that in the WL group was 25.2–53.1%, with an OR of 0.14–0.43.¹⁰ However, there were some differences between this trial and the present study. For example, in that trial, 5-ALA was administered via intravesical injection, and the participants included patients other than those with high-risk NMIBC. However, in our study, the OR of the PDD group to the WL group was 0.46, which is consistent with previously reported findings.

Geavlete et al. performed a randomized controlled trial of PDD-TURBT and WL-TURBT using HAL in 446 high-risk NMIBC cases.⁹ Their results showed that the residual tumor rate at the time of the second TURBT was 31.2% for WL-TURBT and 11.1% for PDD-TURBT, indicating a significantly favorable result for the latter.⁹ However, their definition of “high-risk” was based on the 1973 World Health Organization classification (grades 1–3);¹⁶ therefore, it is difficult to compare their findings with the current results for high-risk NMIBC, which are based on the 2016 World Health Organization classification (low- and high-grade).¹⁷

In our study, the number of tumors, pathological stage, and the presence or absence of concurrent CIS at the time of the first TURBT were prognostic factors for predicting residual tumors at the second TURBT across all cases. These have already been established as risk factors for NMIBC recurrence and progression.¹⁸ Our results are consistent with existing literature. Smoking history has conventionally been reported as an essential risk factor for the development of bladder cancer.¹⁹ Still, in our study, smoking was also identified as a risk factor for residual tumors. Residual tumor rates proportionally increased with the extent of smoking, ranging from 18.8% for nonsmokers to 28.5% for those with a history of smoking and 34.6% for current smokers. In evaluations of the association between smoking and prognosis, cases with current or previous smoking history have been reported to show a significantly shorter recurrence-free survival time compared to nonsmoking cases.²⁰ Because the presence of residual tumors almost certainly reduces the recurrence-free rate, these reports indicate the validity of smoking as a predictive factor for residual tumors. Association between smoking and residual tumor has not been reported and is a subject for future study.

The major adverse reactions reported to date for 5-ALA hydrochloride include liver dysfunction, photosensitivity, and gastrointestinal symptoms (e.g. nausea and vomiting). However, hypotension has recently been reported as a new adverse severe reaction.²¹ In this study, elevated AST or ALT levels, gastrointestinal symptoms, and severe hypotension were reported in 6.3%, 2.6%, and 3.1% of cases, respectively. Adverse reactions of TURBT by oral 5-ALA administration, but no life-threatening severe adverse reactions, were also reported. A randomized controlled trial reported that the incidences of elevated AST levels, elevated ALT levels, gastrointestinal symptoms, and severe hypotension were 24.6%, 11.4%, 4.9%, and 1.6%, respectively,¹⁵ which were similar to those in the present study. These adverse reactions have not been observed in studies from Western countries that have evaluated intravesical injections. However, after considering the patients’ physical distress and medical complexity associated with preanesthesia urethral catheterization, this may be a comparable adverse reaction.

As a PDD, 5-ALA hydrochloride has been used not only for NMIBC but also for malignant glioma, but its usefulness in PDT has also been reported. The administration of 5-ALA, a precursor of PPIX, has been suggested to induce tumor cell-specific accumulation of PPIX in the mitochondria and promote the production of ROS upon irradiation with a specific wavelength of light. ROS accumulation has been reported to induce apoptosis and necrosis in tumor cells.^{22, 23} The efficacy of 5-ALA hydrochloride in PDD against high-risk NMIBC has been shown in this study, but this has also been reported for other cancer types;^{22, 24} the combined use of oral 5-ALA in PDT against NMIBC is expected in the future.

This study had several limitations. First, this was not a randomized controlled trial, and the WL group consisted of retrospectively collected historical data. However, propensity score-matching is thought to facilitate pseudorandomization. Moreover, the residual tumor rate varied at each institution in this multicenter study (data not shown). The residual tumor rate after PDD-TURBT at institutions that enrolled more than 10 patients in this study ranged from 5.1% to 41.6%. However, many participating institutions introduced PDD-TURBT from an early stage following approval for 5-ALA hydrochloride coverage under insurance. Standardization of the technology was achieved to the extent possible by having all institutions watch representative PDD-TURBT video images before the start of this study. The differences between institutions were also thought to reflect real-world differences in the data. In this study, smoking status in the historical group was not investigated. This is a limitation of the study. It is unknown whether the risk factors in this PDD-TURBT group may be adapted in WL-TURBT. In the planning phase of this study, the goal was to prospectively include 200 patients with PDD-TURBT. The final analysis was performed on 188 cases, which were deemed statistically comparable to the historical group. As for the secondary and exploratory endpoints, we are currently in the observation period for recurrence, and the results were excluded from this article.

The odds of residual tumors after the first PDD-TURBT for high-risk NMIBC cases were 0.39 times that after WL-TURBT. Thus, the risk model proposed in this study could be used to omit the second TURBT in approximately a quarter of high-risk NMIBC cases. By performing PDD-TURBT, second-TUR may be omitted for high risk NMIBC without risk factors, which may contribute to reducing patient burden and medical costs. This may also contribute the limited use of operation theaters, which is a great advantage under the influence of the COVID-19 pandemic. We believe statistical decrease of the residual tumor rate should decrease the recurrence rate. Ongoing endpoint of 2-year recurrence-free survival will address the eventual advantage of PDD-TUR as compared with WL-TUR.

Author contributions

Keita Kobayashi: Data curation; Writing – original draft; Writing – review & editing. Hideyasu Matsuyama: Conceptualization; Project administration; Writing – original draft; Writing – review & editing. Taketo Kawai: Data curation. Atsushi Ikeda: Data curation. Makito Miyake: Data curation. Koshiro Nishimoto: Data curation. Yuto Matsushita: Data curation. Kazumasa Komura: Data curation. Takashige Abe: Data curation. Haruki Kume: Supervision. Hiroyuki Nishiyama: Supervision. Kiyohide Fujimoto: Supervision. Masafumi Oyama: Supervision. Hideaki Miyake: Supervision. Keiji Inoue: Supervision. Takahiko Mitsui: Supervision. Mutsushi Kawakita: Supervision. Chikara Ohyama: Supervision. Atsushi Mizokami: Supervision. Hajime Kuroiwa: Formal analysis; Methodology.

Conflict of interest

H. Matsuyama reports personal fees as meeting lecture and grants from SBI Pharmaceuticals Co., Ltd. and Chugai Pharmaceuticals Co., Ltd. H. Nishiyama reports personal fees as consultant and grants from Chugai Pharmaceuticals Co., Ltd. The funding for this study was provided by Chugai Pharmaceutical Co., Ltd. and SBI Pharmaceuticals Co., Ltd. The funding source had no role in the design, practice, or analysis of this study.

Approval of the research protocol by an Institutional Reviewer Board

This study was approved by Ethics Committee of Yamaguchi University (H30-122).

Informed consent

Written informed consent was obtained from all participants.

Registry and the Registration No. of the study/trial

Registration number of UMIN is 000035712.

Animal studies

N/A.