Carcinoma in Situ of the Bladder: Why Is It Underdetected?

José D. Subiela; Óscar Rodr&ıacute; guez Faba; Félix Guerrero-Ramos; Julia Aumatell; Alberto Breda; Joan Palou

Curr Opin Urol. 2020;30(3):392-399.

Abstract and Introduction

Abstract

Purpose of review: The standard diagnosis of carcinoma in situ (CIS) of the bladder, based on white light cystoscopy and urine cytology, is limited because CIS can vary from normal-appearing mucosa to a lesion indistinguishable from an inflammatory process. Intravesical instillation of Bacillus Calmette–Guerin (BCG) remains first-line therapy; however, a significant proportion of cases persist or recur after BCG treatment. This review summarizes recent improvements in the detection and treatment of CIS.

Recent findings: The new optical technologies improve CIS detection, with a potential positive impact on oncological outcomes. The usefulness of MRI-photodynamic diagnosis fusion transurethral resection in CIS detection is unclear and further studies are needed. BCG instillation remains the first-line therapy in CIS patients and seems to improve recurrence and progression rates, especially with the use of maintenance. Intravesical device-assisted therapies could be effective in both BCG-naïve and BCG-unresponsive CIS patients, but further studies are ongoing to clarify their clinical benefit. A phase II clinical trial with pembrolizumab has shown the potential effectiveness of immune checkpoint inhibitors in BCG-unresponsive CIS patients and further trials are ongoing.

Summary: New optical techniques increase the CIS detection rate. BCG instillation remains the first-line treatment. Immune checkpoint inhibitors could be a future alternative in BCG-naïve and BCG-unresponsive CIS patients.

Introduction

Carcinoma in situ (CIS) of the bladder is a high-grade flat lesion limited to the urothelial layer.^[1] A recent meta-analysis in patients with nonmuscle-invasive bladder cancer (NMIBC) who underwent random biopsies showed a pooled incidence of CIS of 17.35%.^[2]

Histopathological and molecular analyses confirm that CIS presents morphometric features similar to muscle invasive bladder cancer (MIBC).^[3] Without treatment, more than 50% of patients progress to MIBC at 5 years of follow-up.^[4]

According to European Association of Urology (EAU) guidelines, CIS may be classified as: primary; CIS without a previous history of bladder cancer; concurrent; CIS in the presence of an exophytic tumor; or secondary; CIS detected during follow-up of a previous tumor that was not CIS.^[5] However, the prognostic impact of this classification remains controversial.^[6,7]

The diagnosis of CIS can be difficult since it can vary from normal-appearing mucosa to a lesion indistinguishable from an inflammatory process; therefore, a pathological report is required for the diagnosis.^[1] However, the introduction of new optical technologies has been shown to improve detection.

The first-line treatment of bladder CIS is Bacillus Calmette–Guerin (BCG) instillation, which has been shown to decrease recurrence and progression, especially with the use of maintenance.^[8] Clinical trials are ongoing to investigate the potential benefit of other agents such as immune checkpoint inhibitors.

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Next Section

Abstract and Introduction
Evidence Acquisition
Current Evidence on Diagnosis of Carcinoma in Situ of the Bladder
Treatment of Carcinoma in Situ of the Bladder
New Perspectives in the Treatment of Carcinoma in Situ
Conclusion
References
Sidebar

Table 1. Summary of the outcomes of the most relevant individual studies using BCG for carcinoma in situ
First author (year) [ref]	Design	No. of CIS patients	Follow-up	Schedule	Strain	CRR	RFS	PFS	OS
Herr (1983) [22]	RCT	17	18 months	TURBT vs. TURBT + BCG 6 weeks	Montreal	N/A	65% (BCG) vs. 8% (TURBT) 1 year	N/A	N/A
DeKernion (1985) [23]	Phase II trial	19	N/A	8 weeks + 12 months	Tice	68%	N/A	N/A	N/A
Lamm (2000) [25]	RCT	278	Until death	6 weeks vs. 6 weeks + 3 weeks/3 years	Connaught	50.7%	41% (6 weeks) vs. 60% (M) 5 years	70% (6 weeks) vs. 76% (M) 5 years	78% (6 weeks) vs. 83% (M) 5 years
Jakse (2001) [29]	Phase II trial	103	91.2 months	6 weeks ( + 6 weeks if no CR)	Connaught	75%	N/A	N/A	N/A
De Reijke (2005) [37]	RCT	168	67 months	BCG (6 weeks + 3 weeks/3 years) vs. epirubicin (8 weeks + 3 weeks/3 years)	Connaught	65% BCG vs. 56% epirubicin	N/A	N/A	N/A
Martínez-Piñeiro (2005) [32]	RCT	65	61 months	BCG (6 weeks + Q2W × 6) SD vs. 1/3D	Connaught	N/A	61.9% (SD) vs. 49.8% (1/3D) 5 years	74.3% (SD) vs. 73.5% (1/3D) 5 years	N/A
Mugiya (2005) [30]	Prospective	43	54 months	BCG 1/2D 6 weeks	Tokyo	84%	61.9% 5 years	N/A	N/A
Takenaka (2008) [27]	Prospective	185	37.5 months	8 weeks	Tokyo	86.5%	66% 5 years	78.5% 5 years	N/A
Gofrit (2009) [26]	Prospective	104	75 months	46% maintenance	Connaught	N/A	63%/54% 5/10 years	79%/77% 5/10 years	N/A
Chade (2010) [6]	Retrospective	130	48 months	6 weeks ( + 6 weeks if no CR)	N/A	62%	27.2% 5 years	17% 5 years	N/A
Koga (2010) [25]	RCT	46	28.7 months	8 weeks vs. 8 weeks + 4 months	Tokyo	77%	74.1% (8 weeks) vs. 95.8% (M) 2 years	No difference	92.6% (8 weeks) vs. 97.1% (M) 2 years
Kaasinen (2016) [41]	RCT	321	119 months	BCG 6 weeks + 10 months vs. Mytomicin C 6 weeks + BCG/MMC 10 months alternating	Connaught	N/A	26% reduction in risk of recurrence (BCG group)	No difference	No difference
Yokomizo (2016) [33]	RCT	155	N/A	8 weeks SD vs. 1/2D	Tokyo	85% SD vs. 78% 1/2D	No difference	No difference	No difference

1/2D, half dose; 1/3D, one third dose; BCG, Bacillus Calmette–Guérin; CIS, carcinoma in situ; CR, complete response; CRR, complete response rate; M, maintenance; N/A, not available; OS, overall survival; PFS, progression-free survival (progression to muscle-invasive disease); RCT, randomised clinical trial; RFS, recurrence-free survival; SD, standard dose; TURBT, transurethral resection of bladder tumor.

Table 2. Current clinical trials investigating the safety and efficacy of immune checkpoint inhibitors in nonmuscle-invasive bladder cancer including carcinoma in situ patients
Clinical trial identifier	Drug	Target	Study design	Phase	Population	Primary end point
NCT03950362	Avelumab	PD-L1	Randomized, open label	I	BCG-unresponsive NMIBC	High-risk RFS
NCT04165317	Sasanlimab	PD-1	Randomized, open label	III	High-risk BCG-naïve NMIBC	Event-free survival
NCT03528694	Durvalumab	PD-L1	Randomized, open label	III	High-risk BCG-naïve NMIBC	Disease-free survival
NCT03711032	Pembrolizumab	PD-1	Randomized, open label	III	BCG-unresponsive NMIBC	CRR
NCT04106115	Durvalumab	PD-L1	Single arm, open label	Ib/II	BCG-unresponsive NMIBC	Pathological disease-free survival and occurrence of dose-limiting toxicity
NCT04134000	Atezolizumab	PD-L1	Single arm, open label	Ib	High-risk BCG-naïve NMIBC	dose limiting toxicity and recurrence free survival
NCT03892642	Avelumab	PD-L1	Single arm, open label	Ib	BCG-unresponsive NMIBC	Dose-limiting toxicity
NCT03759496	Durvalumab	PD-L1	Single arm, open label	II	BCG-unresponsive NMIBC	Maximum tolerated dose, rate of high-grade relapse free
NCT03504163	Pembrolizumab	PD-1	Single arm, open label	II	High-risk BCG-naïve NMIBC	Disease-free survival
NCT03799835	Atezolizumab	PD-L1	Randomized, open label	III	High-risk BCG-naïve NMIBC	RFS
NCT02625961	Pembrolizumab	PD-1	Single arm, open label	II	BCG-unresponsive NMIBC	CRR and disease-free survival
NCT04149574	Nivolumab	PD-1	Randomized, double blind	III	BCG-unresponsive NMIBC	Event-free survival
NCT02792192	Atezolizumab	PD-L1	Single arm, open label	Ib/II	BCG-unresponsive and BCG-relapsing NMIBC	Maximum tolerated dose, adverse events, and CRR
NCT03258593	Durvalumab	PD-L1	Single arm, open label	I	BCG-unresponsive NMIBC	Safety and tolerability
NCT02808143	Pembrolizumab	PD-1	Single arm, open label	I	High-risk BCG-naïve and BCG-refractory NMIBC	Maximum tolerated dose
NCT02844816	Atezolizumab	PD-L1	Single arm, open label	II	BCG-unresponsive NMIBC	CRR
NCT03317158	Durvalumab	PD-L1	Randomized, open label	I/II	BCG-relapsing NMIBC	Maximum tolerated dose, relapse-free survival rates

BCG, Bacillus Calmette –Guérin; CIS, carcinoma in situ; CRR, complete response rate; NMIBC, nonmuscle-invasive bladder cancer; RFS, recurrence-free survival.