
==== Front
World J Urol
World J Urol
World Journal of Urology
0724-4983
1433-8726
Springer Berlin Heidelberg Berlin/Heidelberg

5196
10.1007/s00345-024-05196-7
Original Article
Follow-up strategies after trimodal treatment for muscle-invasive bladder cancer: a systematic review
Kaufmann Ernest 1
Aeppli Stefanie 2
Arnold Winfried 3
Balermpas Panagiotis 4
Beyer Jörg 5
Bieri Uwe 67
Cathomas Richard 8
de Bari Berardino 9
Dressler Marco 10
Engeler Daniel S. 11
Erdmann Andreas 12
Gallina Andrea 13
Gomez Silvia 14
Guckenberger Matthias 4
http://orcid.org/0000-0003-4493-1301
Herrmann Thomas R. W. 151617
Hermanns Thomas 18
Ilaria Lucca 19
John Hubert 20
Kessler Thomas M. 21
Klein Jan 2223
Laouiti Mohamed 24
Lauffer David 25
Mattei Agostino 1
Müntener Michael 26
Nguyen Daniel 27
Niederberger Philipp 28
Papachristofilou Alexandros 29
Prause Lukas 30
Reinhardt Karsten 31
Salati Emanuela 32
Sèbe Philippe 33
Shelan Mohamed 34
Strebel Räto 35
Templeton Arnoud J. 36
Vogl Ursula 37
Wettstein Marian S. 38
Zihler Deborah 39
Zilli Thomas 40
Zwahlen Daniel 41
Roth Beat 42
http://orcid.org/0000-0002-4073-5488
Fankhauser Christian cdfankhauser@gmail.com

1
1 Department of Urology, University of Lucerne, Luzerner Kantonsspital, Spitalstrasse, 6000, 16, Lucerne, Switzerland
2 https://ror.org/00gpmb873 grid.413349.8 0000 0001 2294 4705 Department of Oncology, Kantonsspital St. Gallen, St. Gallen, Switzerland
3 https://ror.org/02zk3am42 grid.413354.4 0000 0000 8587 8621 Department of Radiation-Oncology, Luzerner Kantonsspital, Lucerne, Switzerland
4 https://ror.org/01462r250 grid.412004.3 0000 0004 0478 9977 Department of Radiation-Oncology, Universitiy Hospital Zurich, Zurich, Switzerland
5 grid.411656.1 0000 0004 0479 0855 Department of Oncology, Inselspital Bern, Berne, Switzerland
6 https://ror.org/034e48p94 grid.482962.3 0000 0004 0508 7512 Department of Urology, Kantonsspital Baden, Baden, Switzerland
7 https://ror.org/01462r250 grid.412004.3 0000 0004 0478 9977 Department of Urology, University Hospital Zurich, Zurich, Switzerland
8 Department of Oncology, Kantonsspital Chur, Chur, Switzerland
9 Department of Radiation-Oncology, Réseau Hospitalier Neuchâtelois, Neuchâtel, Switzerland
10 Zentrum Für Onkologie Luzern, Lucerne, Switzerland
11 https://ror.org/00gpmb873 grid.413349.8 0000 0001 2294 4705 Department of Urology, Kantonsspital St. Gallen, St. Gallen, Switzerland
12 https://ror.org/034e48p94 grid.482962.3 0000 0004 0508 7512 Department of Oncology, Kantonsspital Baden, Baden, Switzerland
13 https://ror.org/00sh19a92 grid.469433.f 0000 0004 0514 7845 Department of Urology, EOC Ente Ospedaliero Cantonale, Lugano, Switzerland
14 https://ror.org/056tb3809 grid.413357.7 0000 0000 8704 3732 Department of Radiation-Oncology, Kantonsspital Aarau, Aarau, Switzerland
15 grid.459679.0 0000 0001 0683 3036 Department of Urology, Spital Thurgau AG, Kantonsspital Frauenfeld, Frauenfeld, Switzerland
16 https://ror.org/05bk57929 grid.11956.3a 0000 0001 2214 904X Division of Urology, Department of Surgical Sciences, Stellenbosch University, Western Cape, South Africa
17 https://ror.org/00f2yqf98 grid.10423.34 0000 0000 9529 9877 Hannover Medical School, Hannover, Germany
18 Zentrum für Urologie Zürich, Zurich, Switzerland
19 https://ror.org/05a353079 grid.8515.9 0000 0001 0423 4662 Department of Urology, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland
20 https://ror.org/014gb2s11 grid.452288.1 0000 0001 0697 1703 Department of Urology, Kantonsspital Winterthur, Winterthur, Switzerland
21 https://ror.org/02crff812 grid.7400.3 0000 0004 1937 0650 Department of Neuro-Urology, Balgrist University Hospital, University of Zurich, Zurich, Switzerland
22 https://ror.org/02c28a074 grid.459681.7 0000 0001 2158 1498 Department of Urology, Kantonsspital Münsterlingen, Müsterlingen, Switzerland
23 Department of Urology, Medical School, Ulm, Germany
24 https://ror.org/0431v1017 grid.414066.1 0000 0004 0517 4261 Department of Radiation-Oncology, Hôpital Riviera Chablais, Rennaz, Switzerland
25 https://ror.org/01m1pv723 grid.150338.c 0000 0001 0721 9812 Department of Radiation-Oncology, University Hospital Geneva, Geneva, Switzerland
26 https://ror.org/03kpdys72 grid.414526.0 0000 0004 0518 665X Department of Urology, Stadtspital Triemli, Zurich, Switzerland
27 Department of Urology, Réseau Hospitalier Neuchâtelois, Neuchâtel, Switzerland
28 https://ror.org/02zk3am42 grid.413354.4 0000 0000 8587 8621 Department of Oncology, Luzerner Kantonsspital, Lucerne, Switzerland
29 grid.410567.1 0000 0001 1882 505X Department of Radiation-Oncology, University Hospital Basel, Basel, Switzerland
30 https://ror.org/056tb3809 grid.413357.7 0000 0000 8704 3732 Department of Urology, Kantonsspital Aarau, Aarau, Switzerland
31 Department of Urology, St. Clara Hospital Basel, Basel, Switzerland
32 https://ror.org/0431v1017 grid.414066.1 0000 0004 0517 4261 Department of Oncology, Hôpital Riviera Chablais, Rennaz, Switzerland
33 https://ror.org/01m1pv723 grid.150338.c 0000 0001 0721 9812 Department of Urology, University Hospital Geneva, Geneva, Switzerland
34 grid.411656.1 0000 0004 0479 0855 Department of Radiation-Oncology, Inselspital Bern, Berne, Switzerland
35 Department of Urology, Kantonsspital Chur, Chur, Switzerland
36 https://ror.org/02s6k3f65 grid.6612.3 0000 0004 1937 0642 Department of Oncology, St. Claraspital Basel and Faculty of Medicine, University Basel, Basel, Switzerland
37 https://ror.org/00sh19a92 grid.469433.f 0000 0004 0514 7845 Department of Oncology, EOC Ente Ospedaliero Cantonale, Bellinzona, Switzerland
38 https://ror.org/03dbr7087 grid.17063.33 0000 0001 2157 2938 Department of Uro-Oncology, University of Toronto, Toronto, Canada
39 https://ror.org/056tb3809 grid.413357.7 0000 0000 8704 3732 Department of Oncology, Kantonsspital Aarau, Aarau, Switzerland
40 https://ror.org/00sh19a92 grid.469433.f 0000 0004 0514 7845 Department of Radiation-Oncology, EOC Ente Ospedaliero Cantonale, Bellinzona, Switzerland
41 https://ror.org/014gb2s11 grid.452288.1 0000 0001 0697 1703 Department of Radiation-Oncology, Kantonsspital Winterthur, Winterthur, Switzerland
42 grid.411656.1 0000 0004 0479 0855 Department of Urology, Inselspital Bern, Berne, Switzerland
19 9 2024
19 9 2024
2024
42 1 5278 5 2024
19 7 2024
© The Author(s) 2024
2024
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Purpose

Optimal follow-up strategies following trimodal treatment for muscle invasive bladder cancer play a crucial role in detecting and managing relapse and side-effects. This article provides a comprehensive summary of the patterns and risk factors of relapse, functional outcomes, and follow-up protocols.

Methods

A systematic literature search on PubMed and review of current guidelines and institutional follow-up protocols after trimodal therapy were conducted.

Results

Out of 200 identified publications, 43 studies (28 retrospective, 15 prospective) were selected, encompassing 7447 patients (study sizes from 24 to 728 patients). Recurrence rates in the urinary bladder varied between 14–52%; 3–16% were muscle-invasive while 11–36% were non-muscle invasive. Nodal recurrence occurred at 13–16% and distant metastases at 15–35%. After 5 and 10 years of follow-up, around 60–85% and 45–75% of patients could preserve their bladder, respectively. Various prognostic risk factors associated with relapse and inferior survival were proposed, including higher disease stage (> c/pT2), presence of extensive/multifocal carcinoma in situ (CIS), hydronephrosis, multifocality, histological subtypes, incomplete transurethral resection of bladder tumor (TURBT) and incomplete response to radio-chemotherapy. The analyzed follow-up guidelines varied slightly in terms of the number, timing, and types of investigations, but overall, the recommendations were similar.

Conclusion

Randomized prospective studies should focus on evaluating the impact of specific follow-up protocols on oncological and functional outcomes following trimodal treatment for muscle-invasive bladder cancer. It is crucial to evaluate personalized adaption of follow-up protocols based on established risk factors, as there is potential for improved patient outcomes and resource allocation.

Supplementary Information

The online version contains supplementary material available at 10.1007/s00345-024-05196-7.

Keywords

Trimodal treatment
Trimodality
Bladder preservation
Functional outcomes
Oncological outcomes
Follow-up
University of LuzernOpen access funding provided by University of Luzern

issue-copyright-statement© Springer-Verlag GmbH Germany, part of Springer Nature 2024
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pmcIntroduction

Bladder cancer poses a significant public health challenge, with approximately 500,000 new cases and 200,000 deaths reported annually worldwide [1]. Radical cystectomy represents the most commonly performed therapy for muscle-invasive bladder cancer but may be associated with relevant morbidity and functional impairment leading to a profound impact on patient’s quality of life [2, 3]. Trimodal treatment, consisting of transurethral resection of bladder tumor (TURBT) followed by chemoradiotherapy, has emerged as an alternative approach in selected patients [4]. Numerous studies have suggested comparable long-term survival outcomes between trimodal treatment and radical cystectomy while mitigating perioperative morbidity and preserving patient’s quality of life by bladder preservation [5–10]. With improved treatment protocols, up to 85% of all patients with muscle-invasive bladder cancer can preserve their bladder at 5 years after trimodal treatment [8, 10].

Following trimodal treatment, rigorous post-treatment surveillance is imperative to detect recurrence promptly and allow bladder preservation by repeated TURBT or salvage cystectomy. Monitoring for functional impairments and adverse effects attributed to chemoradiation is also important during and subsequent to the therapy. Presently, clinical evidence guiding the optimal follow-up after trimodal treatment is sparse, with current guidelines largely predicated on consensus from experts. Additionally, while radical cystectomy is associated with marginally elevated costs related to the surgical procedure, the costs of trimodal treatment increase during follow-up, mainly driven by the costs of cystoscopic monitoring [11–14]. Therefore, there is a need to develop tailored surveillance strategies that align with specific treatment modalities and risk profiles, aiming to optimize healthcare expenditure by mitigating redundant diagnostic procedures during follow-up. In this systematic review, we provide a comprehensive summary of the proportion, timing, and anatomical sites of relapse following trimodal treatment, along with the functional complications/toxicities associated with the treatment. Furthermore, we discuss published follow-up protocols and explore current and future developments in the follow-up care of patients who have undergone trimodal treatment.

Evidence acquisition

We conducted a systematic literature search on PubMed on February 22, 2024, in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement to identify published follow-up protocols for patients who have undergone trimodal treatment for bladder cancer (see Supplementary File 1). This systematic review was registered with PROSPERO, the international prospective register for systematic reviews (registration number: CRD42024525165).

Our search included (1) current guidelines from the American Urology, Oncology and Radiation Oncology Associations (AUA/ASCO/ASTRO/SUO), Bladder Cancer Canada, the European Association of Urology (EAU), the European Society for Medical Oncology (ESMO), the German S3-guideline, the National Comprehensive Cancer Network (NCCN) and (2) follow-up protocols of published networks or institutions. We excluded non-English literature (with exception of the German S3-Guidelines) and publications before 1990. We manually screened the reference lists of identified publications to find additional relevant studies, and we used Endnote’s ‘close match’ function to filter out duplicate articles. One investigator (EK) screened all titles, abstracts, and full texts for inclusion in the study. Data from the same study that appeared in multiple publications were only included once. Finally, we only included published manuscripts containing a minimum of 20 patients in the analysis. To reduce risk of bias and resolve any discrepancies, a second investigator (CDF) was involved in the screening process.

Evidence synthesis

We identified 200 publications that met our initial search criteria, and we conducted a title and abstract screening of 92 full texts (Supplementary Fig. 1). After screening, we included 43 studies in our analysis, of which 28 were retrospective and 15 were prospective (see Supplementary Table 1). These 43 studies included a range of 24–728 patients, providing data for a total of 7447 patients.

Optimal diagnostic testing for oncological follow-up

The primary objective of oncological follow-up after trimodal treatment is to identify any signs of local or systemic recurrence and to screen for secondary malignancies that are frequently associated with bladder cancer, such as urothelial carcinomas of the urethra or upper urinary tract, as well as lung cancer, particularly in individuals who are current or former smokers. Given the variability in accuracy among different imaging modalities in detecting these recurrences, current guidelines advocate for the use of multiple modalities in follow-up imaging. Cystoscopy and cytology are recommended for detecting local recurrences, while cross-sectional imaging techniques such as computerized tomography (CT), magnetic resonance imaging (MRI), or 18F-fluorodeoxyglucose positron emission tomography (FDG-PET-CT) are recommended to identify both local recurrence and distant metastases [15].

Cross-sectional imaging

No comparative studies comparing different cross-sectional imaging modalities or specific time-points for follow-up after trimodal treatment for muscle-invasive bladder cancer have been identified. As a result, most guidelines for follow-up protocols are derived from cystectomy follow-up protocols [16]. The current recommendations of recognized guidelines are summarized in Table 1. The American Urological Association (AUA) suggests CT or MRI of the abdomen and pelvis, along with chest imaging, every 6 months during the first 2 years, and subsequently on an annual basis [17]. According to the European Association of Urology (EAU) and the European Society for Medical Oncology (ESMO), CT of the chest and abdomen should be conducted every 3–4 months during the first 2 years, followed by imaging every 6–12 months until the 5th year [18, 19]. As for the German S3-Guidelines, they recommend CT of the chest and abdomen every 6 months for 2–3 years, followed by annual imaging until the 5th year [20]. The National Comprehensive Cancer Network (NCCN) recommends CT urography (CTU) or MR urography (MRU) of the abdomen and pelvis, including thoracic CT, every 3–6 months in the first 2 years, and then annually until the 5th year [15]. It should be mentioned that only the NCCN recommends FDG-PET-CT in their guidelines.Table 1 Comparison of different oncological follow-up schedules including investigations and their intervals in between (in months) after trimodal therapy for bladder cancer

MIBC	Months after TMT	3	6	9	12	15	18	21	24	27	30	33	36	42	48	54	60	61–120	
AUA	visit	(x)	x	(x)	x	(x)	x	(x)	x				x		x		x		
CT Chest		x		x		x		x										
CT or MRI Abd/Pelv		x		x		x		x										
Cystoscopy	x	x	x	x	(x)	x	(x)	x		(x)		x	(x)	x	(x)	x		
Cytology	?																	
BLADDER CANCER CANADA	visit	x	x	x	x	x	x	x	x		x		x	x	x		x	Annually	
chest x-ray or CT Thorax		x’		x		x’		x		x´´		x	x´´	x	x´´	x		
CT Abdomen		x’		x		x’		x				x		x’		x		
Cystoscopy	x	x	x	x	x	x	x	x		x		x	x	x		x	Annually	
Cytology				(x)				(x)				(x)		(x)		(x)		
EAU	visit	x	x	x	x	x	x	x	x	x	x	x	x	x	x	x	x		
CT Chest		x		x		x		x				x		x		x		
CT Abd/Pelv		x		x		x		x				x		x		x		
Cystoscopy	x	x	x	x	x	x	x	x	x	x	x	x	x	x	x	x		
Cytology		x		x		x		x		x		x	x	x	x	x		
ESMO	visit	x	x	x	x	x	x	x	x		x		x	x	x	x	x		
CT Chest	x	x	x	x	x	x	x	x		(x)		x	(x)	x	(x)	x		
CT Abd/Pelv	x	x	x	x	x	x	x	x		x		x	x	x	x	x		
Cystoscopy	(x)	x	(x)	x	(x)	x	(x)	x	(x)	x	(x)	x	x	x	x	x		
Cytology	?																	
GERMAN S3 GUIDELINE	visit	x	x	x	x	x	x	x	x	x	x	x	x	x	x	x	x	Annually	
CT Chest	x	x		x		x		x		x		x		x		x		
CT Abdomen	x	x		x		x		x		x		x		x		x		
Cystoscopy	x	x	x	x	x	x	x	x	x	x	x	x	x	x	x	x	Annually	
Cytology	x	x	x	x	x	x	x	x	x	x	x	x	x	x	x	x		
NCCN	visit	x	x	x	x	x	x	x	x		x		x	x	x		x	Annually	
CT Chest (or chest x-ray)	(x)	X	(x)	x	(x)	x	(x)	x										
CTU Abd/Pelv (or MRU)a,b	(x)	X	(x)	x	(x)	x	(x)	x				x		x		x		
Cystoscopy	x	x	x	x	x	x	x	x		x		x	x	x		x	Annually	
Cytology		(x)		x		(x)		x										
aCTU/MRU image upper tracts + axial imaging of abdomen/pelvis only in years 1 + 2

bFDG PET/CT (category 2B) only if metastatic disease suspected

? investigation recommended without exact time schedule

X’ and X’’ Bladder Cancer Canada recommends the same imaging studies and intervals for TMT as for cystectomy, there it differs between < / = pT2 (x), pT3-4 (X’) and pTxN + (X’’)

(x) Optional

Ultrasound

Ultrasonography of the kidneys after trimodal treatment is not recommended by any guideline.

Cystoscopy and cytology

Cystoscopy in patients who have undergone trimodal treatment for muscle-invasive bladder cancer can be challenging due to morphological alterations mainly caused by radiation effects. These alterations often make it difficult to differentiate between malignant changes in the bladder and post-radiation changes such as fibrosis, pseudopapillary inflammation, and epithelial denudation, which are commonly observed [21]. Compared to patients without prior radiotherapy to the bladder, the specificity and positive predictive value to find a relapse after radiotherapy were reported as 88 and 40%, while without radiotherapy they were 90 and 77%, respectively [22]. Similarly, the diagnostic accuracy of cytology is also modified in trimodal treatment patients with a limited sensitivity and specificity of 50 and 85% [22]. Nearly all patients show abnormal cytology early after treatment but it normalizes in over half of the patients within the first 3 months [23]. Remarkably, most studies do not differentiate between spontaneous and bladder wash cytology. A modelling study using prospectively collected data suggests that monitoring symptoms such as haematuria and urgency, alongside urine cytology, may effectively reduce the number of cystoscopies required during follow-up [24].

Although there is limited strong data to support routine cytology, guidelines recommend its use, albeit with variations in timing. The American Urological Association (AUA) suggests cystoscopy every 3 months during the first year, every 4–6 months in the second year, and every 6–12 months thereafter. Cytology is also recommended but without a specific time schedule [17]. The European Association of Urology (EAU) and the German S3-guidelines suggest cystoscopy with regular cytology every 3–4 months during the first 3 years and every 6 months until the 5th year [18]. Additionally, the German S3-guidelines mention that annual cystoscopies should be performed after the 5th year and that a biopsy from each suspicious cystoscopy finding should be taken [20]. The European Society for Medical Oncology (ESMO) recommends cystoscopies every 3–6 months for the first 5 years [19]. The National Comprehensive Cancer Network (NCCN) and Bladder Cancer Canada recommend cystoscopy every 3 months in years 1–2, every 6 months in years 3–4, and annually in years 5–10. Bladder Cancer Canada emphasizes urine cytology at every cystoscopy, while the NCCN recommends cytology only every 6–12 months in the first 2 years and thereafter only if clinically indicated [15, 25]. Biopsies of the tumor site are suggested in several institutional follow-up protocols [7, 8, 26–29], but not mentioned in any other guidelines.

Emerging biomarkers

Emerging biomarkers offer significant promise in improving the precision of disease stage assessment, monitoring therapeutic responses, and reducing the frequency and costs of traditional follow-up procedures in bladder cancer management [30–34]. Promising biomarkers for recurrence detection represent tumour informed ctDNA (NCT05630131), Bladder CARE™ [35], UroAmp [36, 37], and microRNAs [38].

Disease-specific risk factors for worse outcomes and recurrence

Numerous clinical variables like T-stage [7, 8], N-stage [39], cytology during follow-up [23] multifocality [40], completeness of TURBT [7, 26, 27], hydronephrosis [7, 41] or presence of different histological subtypes [41, 42] have an influence on the risk for recurrence.

Disease-specific recurrence patterns

Within 2–10 years after trimodal treatment, 14–52% experience local recurrence in the bladder as the most common relapse site (11–36% non-muscle invasive, 3–16% muscle invasive), 15–35% distant metastases, and 13–16% nodal recurrence [7, 8, 10, 43–45]. Five and 10 years after trimodal treatment, non-muscle-invasive recurrence, muscle-invasive recurrence, and distant metastases were estimated to be 31 and 36, 13 and 14, and 31 and 35%, respectively [7]. Distant recurrence is found in the lungs in 6%, in the bones in 3–8%, the adrenal glands in 6%, in non-regional lymph nodes in 14%, and recurrence in regional pelvic lymph nodes in 3–8% of the cases [9, 10, 46]. The median time from completion of trimodal treatment to detection of local non-muscle invasive relapse is 2 years [47], with most muscle-invasive and metastatic recurrences occurring within the first 5 years of follow-up. Recurrences beyond 5 years are uncommon [7] but still possible: nearly 10% of all non-muscle invasive relapses occur later than 10 years after the initial treatment with complete response [28]. However, these late relapses may not only arise from recurrences but also from secondary cancers in the context of field cancerization.

Functional follow-up/quality of life

Trimodal treatment has the potential to maintain overall quality of life, including aspects related to general well-being, body image, and the mitigation of negative effects, along with favorable outcomes concerning bowel and sexual quality of life [48, 49]. This is supported by bladder preservation rates of 60–87% at 5 years post-treatment, and 45–76% at 10 years [10, 27, 41]. Nonetheless, it is crucial to consider and discuss the side effects related to the treatment [3].

Common short-term genitourinary side effects, such as hematuria and dysuria, caused by radiation cystitis are generally of minor severity (CTCAE grades 1–2), affecting 20–65% of patients [9, 44]. Long-term toxicities of various severity grades, including diminished bladder capacity, urgency, incontinence, and urinary leakage, have been reported at rates of 25, 15, 19, and 19%, respectively, during follow-up [49]. Post-radiation urodynamic studies highlight significant compliance reduction and decreased maximum cytometric capacity [50, 51]. In addition, urinary tract infections are common after trimodal treatment [50, 51]. While severe complications like urethral strictures or hydronephrosis are uncommon [52], urinary symptoms such as urgency or incontinence are up to three times more prevalent in women compared to men [49]. Furthermore, late genitourinary toxicities of a significant severity (Grade 3–4) may differ among the different radiotherapy fractionation-regimens [43]. Only a minor proportion of patients report distress caused by gastrointestinal late complications with 9% of the affected patients reporting a moderate or greater distress caused by diarrhoea and 14% by bowel urgency [49]. In a study by Efstathiou et al. from 2009 looking at four RTOG trials, low rates of severe (≥ Grade 3) late pelvic (genitourinary or gastrointestinal) toxicities were seen for patients completing trimodal treatment and retaining their native bladder [29].

Based on long-term data from radiotherapy in prostate cancer reporting rates of fecal incontinence of up to 10%, there are concerns that similar or even worse outcomes could be observed after trimodal treatment, however there are only limited long-term data, especially from cohorts treated with modern radiotherapy techniques [53]. Therefore, novel radiotherapy techniques are explored including intensity-modulated radiotherapy (IMRT), the more recently developed volumetric-modulated arc therapy (VMAT) or even adaptive radiotherapy (ART); they have an improved dose homogeneity and sparing of the bladder, rectum, and pelvis and might reduce toxicities [54]. This potentially positive effect must be confirmed in comparative clinical trials. First results are promising as in a prospective trial only 20% of the patients suffered from acute grade ≥ 2 gastrointestinal toxicity and 16% had grade ≥ 2 genitourinary toxicities when receiving VMAT [55]. In addition, ART could further decrease toxicity [54]. Recently published results of the RAIDER Trial (NCT02447549) have shown that standard dose adaptive tumor focused radiotherapy (SART) and dose escalated adaptive tumor boost radiotherapy (DART) had lower Grade ≥ 2/3 late toxicity compared to standard whole bladder radiotherapy (WBRT). Grade ≥ 2/3 late toxicity rates 6–18 months after trimodal therapy were significantly reduced by DART (42%/9%, 35%/4%, and 32%/6% for WBRT, SART, and DART) [56].

Discussion and conclusion

This systematic review examines trimodal treatment in the context of muscle-invasive bladder cancer, aggregating findings on follow-up assessments, the location and timing of recurrence stratified by disease stage and contrasting the follow-up protocols delineated in various guidelines. Our analysis reveals that existing follow-up recommendations are predicated on a limited evidence base. There is a clinical need to enhance follow-up personalization by tailoring it to an individual's recurrence risk. Additionally, there is scope for future research to integrate novel biomarkers, aiming to bolster oncological outcomes and curtail healthcare expenditures.

Trimodal treatment is commonly employed in two distinct populations: patients with adequate bladder function who prefer bladder preservation, and frail patients who are not suitable for surgery. Surprisingly, many studies demonstrate comparable outcomes of radical cystectomy versus trimodal treatment in patients who are medically fit enough for both treatment strategies, but in daily clinical practice trimodal treatment is often not even offered to all patients. but rather to the frail patient population only. In patients with adequate bladder function who prefer bladder preservation, there is an unmet need for research addressing the question of functional outcomes specifically dedicated to bladder related wellbeing and symptoms by means of patient reported outcome measures (PROMs/questionnaires), management of radiation-induced lower urinary tract dysfunction and the development of safe follow-up protocols enabling timely salvage cystectomy. For instance, investigating surveillance of the lower and upper urinary tract using innovative MRI protocols, CT, or ultrasonography or novel biomarkers should be explored. It should also be noted, that with the continuous innovation, and personalization of treatment strategies, such as the use of new radiotherapy techniques (IMRT, VMAT, adaptive radiotherapy), oncological outcomes as well as toxicity profiles could be improved. Consequently, the development of personalized surveillance protocols is needed to adapt to these evolving treatment approaches. In contrast, frail patients require a goal-directed surveillance approach that takes into account the limited therapeutic consequences and incorporates competing risks such as age, comorbidities (e.g., geriatric assessment, malnutrition) and other survival surrogates to offer individually tailored surveillance strategies based on their risk profiles.

In this systematic review focusing on follow-up strategies post-trimodal treatment for muscle-invasive bladder cancer, we highlighted the need for personalized follow-up approaches, given the current recommendations are based on limited evidence. Our examination suggests the potential for individualized protocols that factor in patient-specific risks of recurrence, coupled with the integration of novel biomarkers, to enhance oncological outcomes and optimize healthcare resources. Such tailored strategies promise not only to improve patient monitoring and intervention timeliness but also to contribute to cost-effective healthcare management in the context of bladder cancer post-treatment surveillance.

Take home message

Guideline recommendations and institutional follow-up protocols after trimodal treatment only slightly differ regarding the modality, intensity, and timing of follow-up investigations, but are not personalized to the various risk factors for relapse, which can possibly lead to suboptimal care of bladder cancer survivors. More prospective trials are needed to assess how bladder cancer patients can be followed after trimodal treatment in order to ensure optimal oncological and functional outcomes. Furthermore, the role of PROMs/questionnaires and novel biomarkers during follow-up should be defined and new protocols implementing new therapeutic modalities such as adaptive radiotherapy and immunotherapies should be developed.

Supplementary Information

Below is the link to the electronic supplementary material.Supplementary file1 (PDF 304 KB)

Supplementary file2 (PDF 164 KB)

Supplementary file3 (PDF 250 KB)

Author’s contribution

E. Kaufmann: project development, literature search, Data collection, Data analysis, Manuscript writing/editing, C. Fankhauser: project development, Data collection, Data analysis, Manuscript writing/editing, S. Aeppli, W. Arnold, P. Balermpas, J. Beyer, U. Bieri, R. Cathomas, B. De Bari, M. Dressler, DS Engeler, A. Erdmann, A. Gallina, S. Gomez, M. Guckenberger, T. Hermanns, L. Ilaria, H. John, TM. Kessler, J. Klein, M. Laouiti, D. Lauffer, A. Mattei, M. Müntener, D. Nguyen, P. Niederberger, A. Papachristofilou, L. Prause, K. Reinhardt, E. Salati, P. Sèbe, M. Shelan, R. Strebel, AJ. Templeton, U. Vogl, MS. Wettstein, D. Zihler, T. Zilli, D. Zwahlen, B. Roth: Data analysis, Manuscript writing/editing.

Funding

Open access funding provided by University of Luzern. No funding was received.

Data availability

All data supporting the findings of this study are available within the paper and its Supplementary Information.

Declarations

Conflict of interest

The authors declare no competing interests.

Consent for publication

All patients provided written consent.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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References

1. Lenis AT Lec PM Chamie K Mshs MD Bladder cancer: a review JAMA 2020 324 1980 1991 10.1001/jama.2020.17598 33201207
Lenis AT, Lec PM, Chamie K, Mshs MD (2020) Bladder cancer: a review. JAMA 324:1980–1991. 10.1001/jama.2020.1759833201207
2. Catto JWF Downing A Mason S Wright P Absolom K Bottomley S Quality of life after bladder cancer: a cross-sectional survey of patient-reported outcomes Eur Urol 2021 79 621 632 10.1016/j.eururo.2021.01.032 33581875
Catto JWF, Downing A, Mason S, Wright P, Absolom K, Bottomley S et al (2021) Quality of life after bladder cancer: a cross-sectional survey of patient-reported outcomes. Eur Urol 79:621–632. 10.1016/j.eururo.2021.01.03233581875
3. Mak KS Smith AB Eidelman A Clayman R Niemierko A Cheng JS Quality of life in long-term survivors of muscle-invasive bladder cancer Int J Radiat Oncol Biol Phys 2016 96 1028 1036 10.1016/j.ijrobp.2016.08.023 27727064
Mak KS, Smith AB, Eidelman A, Clayman R, Niemierko A, Cheng JS et al (2016) Quality of life in long-term survivors of muscle-invasive bladder cancer. Int J Radiat Oncol Biol Phys 96:1028–1036. 10.1016/j.ijrobp.2016.08.02327727064
4. James ND Hussain SA Hall E Jenkins P Tremlett J Rawlings C Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer N Engl J Med 2012 366 1477 1488 10.1056/NEJMoa1106106 22512481
James ND, Hussain SA, Hall E, Jenkins P, Tremlett J, Rawlings C et al (2012) Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer. N Engl J Med 366:1477–1488. 10.1056/NEJMoa110610622512481
5. Softness K, Kaul S, Fleishman A, Efstathiou J, Bellmunt J, Kim SP et al. (2022) Radical cystectomy versus trimodality therapy for muscle-invasive urothelial carcinoma of the bladder. Urol Oncol. 40: 272. 10.1016/j.urolonc.2021.12.015
6. Kulkarni GS Hermanns T Wei Y Bhindi B Satkunasivam R Athanasopoulos P Propensity score analysis of radical cystectomy versus bladder-sparing trimodal therapy in the setting of a multidisciplinary bladder cancer clinic J Clin Oncol 2017 35 2299 2305 10.1200/jco.2016.69.2327 28410011
Kulkarni GS, Hermanns T, Wei Y, Bhindi B, Satkunasivam R, Athanasopoulos P et al (2017) Propensity score analysis of radical cystectomy versus bladder-sparing trimodal therapy in the setting of a multidisciplinary bladder cancer clinic. J Clin Oncol 35:2299–2305. 10.1200/jco.2016.69.232728410011
7. Mak RH Hunt D Shipley WU Efstathiou JA Tester WJ Hagan MP Long-term outcomes in patients with muscle-invasive bladder cancer after selective bladder-preserving combined-modality therapy: a pooled analysis of Radiation Therapy Oncology Group protocols 8802, 8903, 9506, 9706, 9906, and 0233 J Clin Oncol 2014 32 3801 3809 10.1200/jco.2014.57.5548 25366678
Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP et al (2014) Long-term outcomes in patients with muscle-invasive bladder cancer after selective bladder-preserving combined-modality therapy: a pooled analysis of Radiation Therapy Oncology Group protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol 32:3801–3809. 10.1200/jco.2014.57.554825366678
8. Giacalone NJ Shipley WU Clayman RH Niemierko A Drumm M Heney NM Long-term outcomes after bladder-preserving tri-modality therapy for patients with muscle-invasive bladder cancer: an updated analysis of the massachusetts general hospital experience Eur Urol 2017 71 952 960 10.1016/j.eururo.2016.12.020 28081860
Giacalone NJ, Shipley WU, Clayman RH, Niemierko A, Drumm M, Heney NM et al (2017) Long-term outcomes after bladder-preserving tri-modality therapy for patients with muscle-invasive bladder cancer: an updated analysis of the massachusetts general hospital experience. Eur Urol 71:952–960. 10.1016/j.eururo.2016.12.02028081860
9. Kobayashi K Matsumoto H Misumi T Ito H Hirata H Nagao K The efficacy of trimodal chemoradiotherapy with gemcitabine and cisplatin as a bladder-preserving strategy for the treatment of muscle-invasive bladder cancer: a single-arm phase II study Jpn J Clin Oncol 2022 52 1201 1207 10.1093/jjco/hyac095 35675636
Kobayashi K, Matsumoto H, Misumi T, Ito H, Hirata H, Nagao K et al (2022) The efficacy of trimodal chemoradiotherapy with gemcitabine and cisplatin as a bladder-preserving strategy for the treatment of muscle-invasive bladder cancer: a single-arm phase II study. Jpn J Clin Oncol 52:1201–1207. 10.1093/jjco/hyac09535675636
10. Zlotta AR Ballas LK Niemierko A Lajkosz K Kuk C Miranda G Radical cystectomy versus trimodality therapy for muscle-invasive bladder cancer: a multi-institutional propensity score matched and weighted analysis Lancet Oncol 2023 24 669 681 10.1016/s1470-2045(23)00170-5 37187202
Zlotta AR, Ballas LK, Niemierko A, Lajkosz K, Kuk C, Miranda G et al (2023) Radical cystectomy versus trimodality therapy for muscle-invasive bladder cancer: a multi-institutional propensity score matched and weighted analysis. Lancet Oncol 24:669–681. 10.1016/s1470-2045(23)00170-537187202
11. Williams SB Shan Y Ray-Zack MD Hudgins HK Jazzar U Tyler DS Comparison of costs of radical cystectomy vs trimodal therapy for patients with localized muscle-invasive bladder cancer JAMA Surg 2019 154 e191629 10.1001/jamasurg.2019.1629 31166593
Williams SB, Shan Y, Ray-Zack MD, Hudgins HK, Jazzar U, Tyler DS et al (2019) Comparison of costs of radical cystectomy vs trimodal therapy for patients with localized muscle-invasive bladder cancer. JAMA Surg 154:e191629. 10.1001/jamasurg.2019.162931166593
12. Golla V, Shan Y, Farran EJ, Stewart CA, Vu K, Yu A, et al. (2022) Long term cost comparisons of radical cystectomy versus trimodal therapy for muscle-invasive bladder cancer. Urol Oncol. 40: 273.e1-.e9. 10.1016/j.urolonc.2022.01.007
13. Suskovic N, Raldow AC, Royce TJ, Smith A (2020) Cost-effectiveness of radical cystectomy versus trimodality therapy for muscle invasive bladder cancer. J Clin Oncol. 38: 575. 10.1200/JCO.2020.38.6_suppl.575
14. Kool R, Yanev I, Hijal T, Vanhuyse M, Cury FL, Souhami L, et al. (2022) Trimodal therapy vs. radical cystectomy for muscle-invasive bladder cancer: A Canadian cost-effectiveness analysis. Canadian Urological Association journal = Journal de l'Association des urologues du Canada; 16:189–98. 10.5489/cuaj.7430
15. Flaig TW, Spiess PE, Agarwal N, Bangs R, Boorjian SA, Buyyounouski MK et al. (2020) Bladder cancer, version 3.2020, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 18: 329-354. 10.6004/jnccn.2020.0011
16. Kaufmann E Black PC Catto JW Djaladat H Ghodoussipour S Hamilton-Reeves JM Oncological surveillance after radical cystectomy, a narrative review of the enhanced recovery after surgery (ERAS) cystectomy committee 2023 JU Open Plus In Press
Kaufmann E, Black PC, Catto JW, Djaladat H, Ghodoussipour S, Hamilton-Reeves JM et al (2023) Oncological surveillance after radical cystectomy, a narrative review of the enhanced recovery after surgery (ERAS) cystectomy committee. In Press, JU Open Plus
17. Chang SS Bochner BH Chou R Dreicer R Kamat AM Lerner SP Treatment of non-metastatic muscle-invasive bladder cancer: AUA/ASCO/ASTRO/SUO Guideline J Urol 2017 198 552 559 10.1016/j.juro.2017.04.086 28456635
Chang SS, Bochner BH, Chou R, Dreicer R, Kamat AM, Lerner SP et al (2017) Treatment of non-metastatic muscle-invasive bladder cancer: AUA/ASCO/ASTRO/SUO Guideline. J Urol 198:552–559. 10.1016/j.juro.2017.04.08628456635
18. Witjes JA Bruins HM Cathomas R Compérat EM Cowan NC Gakis G European Association of Urology Guidelines on muscle-invasive and metastatic bladder cancer: summary of the 2020 Guidelines Eur Urol 2021 79 82 104 10.1016/j.eururo.2020.03.055 32360052
Witjes JA, Bruins HM, Cathomas R, Compérat EM, Cowan NC, Gakis G et al (2021) European Association of Urology Guidelines on muscle-invasive and metastatic bladder cancer: summary of the 2020 Guidelines. Eur Urol 79:82–104. 10.1016/j.eururo.2020.03.05532360052
19. Powles T Bellmunt J Comperat E De Santis M Huddart R Loriot Y Bladder cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up Ann Oncol 2022 33 244 258 10.1016/j.annonc.2021.11.012 34861372
Powles T, Bellmunt J, Comperat E, De Santis M, Huddart R, Loriot Y et al (2022) Bladder cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol 33:244–258. 10.1016/j.annonc.2021.11.01234861372
20. (2020) S3-Leitlinie Früherkennung, diagnose, therapie und nachsorge des harnblasenkarzinoms. AWMF Online das portal der wissenschaftlichen Medizin; Version 2.0 März 2020: 330-1
21. Evaristo G Khadang B Kool R Marcq G Farag MS Kassouf W Morphologic alterations post trimodal therapy in muscle-invasive urothelial carcinoma: understanding the impact of post-treatment changes on the pathological interpretation and their potential clinical correlates Hum Pathol 2022 126 2 8 10.1016/j.humpath.2022.04.013 35490858
Evaristo G, Khadang B, Kool R, Marcq G, Farag MS, Kassouf W et al (2022) Morphologic alterations post trimodal therapy in muscle-invasive urothelial carcinoma: understanding the impact of post-treatment changes on the pathological interpretation and their potential clinical correlates. Hum Pathol 126:2–8. 10.1016/j.humpath.2022.04.01335490858
22. van Rhijn BW Smit M van Geenen D Wijnmaalen A Kirkels WJ van der Kwast TH Surveillance with microsatellite analysis of urine in bladder cancer patients treated by radiotherapy Eur Urol 2003 43 369 373 10.1016/s0302-2838(03)00059-9 12667717
van Rhijn BW, Smit M, van Geenen D, Wijnmaalen A, Kirkels WJ, van der Kwast TH et al (2003) Surveillance with microsatellite analysis of urine in bladder cancer patients treated by radiotherapy. Eur Urol 43:369–373. 10.1016/s0302-2838(03)00059-912667717
23. McLoughlin LC, O’Halloran S, Tjong M, Ajib K, Lajkosz K, Ruff H et al. (2022) The prognostic value of urinary cytology after trimodal therapy (TMT) for muscle-invasive bladder cancer. Urol Oncol. 40: 346.e9-.e16. 10.1016/j.urolonc.2022.02.021
24. Krishnatry R Maitre P Kumar A Telkhade T Bakshi G Prakash G Utilising alternative cystoscopic schedules to minimise cost and patient burden after trimodality therapy for muscle-invasive bladder cancer Cancer Med 2023 12 11305 11314 10.1002/cam4.5840 36965102
Krishnatry R, Maitre P, Kumar A, Telkhade T, Bakshi G, Prakash G et al (2023) Utilising alternative cystoscopic schedules to minimise cost and patient burden after trimodality therapy for muscle-invasive bladder cancer. Cancer Med 12:11305–11314. 10.1002/cam4.584036965102
25. Kassouf W, Aprikian A, Black P, Kulkarni G, Izawa J, Eapen L et al. (2016) Recommendations for the improvement of bladder cancer quality of care in Canada: a consensus document reviewed and endorsed by Bladder Cancer Canada (BCC), Canadian Urologic Oncology Group (CUOG), and Canadian Urological Association (CUA), December 2015. Canad Urol Assoc J. 10: E46-80. 10.5489/cuaj.3583
26. Rödel C Grabenbauer GG Kühn R Papadopoulos T Dunst J Meyer M Combined-modality treatment and selective organ preservation in invasive bladder cancer: long-term results J Clin Oncol 2002 20 3061 3071 10.1200/jco.2002.11.027 12118019
Rödel C, Grabenbauer GG, Kühn R, Papadopoulos T, Dunst J, Meyer M et al (2002) Combined-modality treatment and selective organ preservation in invasive bladder cancer: long-term results. J Clin Oncol 20:3061–3071. 10.1200/jco.2002.11.02712118019
27. Efstathiou JA Spiegel DY Shipley WU Heney NM Kaufman DS Niemierko A Long-term outcomes of selective bladder preservation by combined-modality therapy for invasive bladder cancer: the MGH experience Eur Urol 2012 61 705 711 10.1016/j.eururo.2011.11.010 22101114
Efstathiou JA, Spiegel DY, Shipley WU, Heney NM, Kaufman DS, Niemierko A et al (2012) Long-term outcomes of selective bladder preservation by combined-modality therapy for invasive bladder cancer: the MGH experience. Eur Urol 61:705–711. 10.1016/j.eururo.2011.11.01022101114
28. Sanchez A Wszolek MF Niemierko A Clayman RH Drumm M Rodríguez D Incidence, clinicopathological risk factors, management and outcomes of nonmuscle invasive recurrence after complete response to trimodality therapy for muscle invasive bladder cancer J Urol 2018 199 407 415 10.1016/j.juro.2017.08.106 28870862
Sanchez A, Wszolek MF, Niemierko A, Clayman RH, Drumm M, Rodríguez D et al (2018) Incidence, clinicopathological risk factors, management and outcomes of nonmuscle invasive recurrence after complete response to trimodality therapy for muscle invasive bladder cancer. J Urol 199:407–415. 10.1016/j.juro.2017.08.10628870862
29. Efstathiou JA Bae K Shipley WU Kaufman DS Hagan MP Heney NM Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89–03, 95–06, 97–06, 99–06 J Clin Oncol 2009 27 4055 4061 10.1200/jco.2008.19.5776 19636019
Efstathiou JA, Bae K, Shipley WU, Kaufman DS, Hagan MP, Heney NM et al (2009) Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89–03, 95–06, 97–06, 99–06. J Clin Oncol 27:4055–4061. 10.1200/jco.2008.19.577619636019
30. Birkenkamp-Demtröder K Christensen E Nordentoft I Knudsen M Taber A Høyer S Monitoring treatment response and metastatic relapse in advanced bladder cancer by liquid biopsy analysis Eur Urol 2018 73 535 540 10.1016/j.eururo.2017.09.011 28958829
Birkenkamp-Demtröder K, Christensen E, Nordentoft I, Knudsen M, Taber A, Høyer S et al (2018) Monitoring treatment response and metastatic relapse in advanced bladder cancer by liquid biopsy analysis. Eur Urol 73:535–540. 10.1016/j.eururo.2017.09.01128958829
31. Birkenkamp-Demtröder K Nordentoft I Christensen E Høyer S Reinert T Vang S Genomic alterations in liquid biopsies from patients with bladder cancer Eur Urol 2016 70 75 82 10.1016/j.eururo.2016.01.007 26803478
Birkenkamp-Demtröder K, Nordentoft I, Christensen E, Høyer S, Reinert T, Vang S et al (2016) Genomic alterations in liquid biopsies from patients with bladder cancer. Eur Urol 70:75–82. 10.1016/j.eururo.2016.01.00726803478
32. Powles T Assaf ZJ Davarpanah N Banchereau R Szabados BE Yuen KC ctDNA guiding adjuvant immunotherapy in urothelial carcinoma Nature 2021 595 432 437 10.1038/s41586-021-03642-9 34135506
Powles T, Assaf ZJ, Davarpanah N, Banchereau R, Szabados BE, Yuen KC et al (2021) ctDNA guiding adjuvant immunotherapy in urothelial carcinoma. Nature 595:432–437. 10.1038/s41586-021-03642-934135506
33. Carrasco R, Ingelmo-Torres M, Gómez A, Trullas R, Roldán FL, Ajami T, et al. (2022) Cell-free DNA as a prognostic biomarker for monitoring muscle-invasive bladder cancer. Int J Mol Sci. 23: 11732. 10.3390/ijms231911732
34. Powles TB Gschwend JE Bracarda S Castellano D Gross-Goupil M Bjerggaard Jensen J 716TiP IMvigor011: a global, double-blind, randomised phase III study of atezolizumab (atezo; anti–PD-L1) vs placebo (pbo) as adjuvant therapy in patients (pts) with high-risk muscle-invasive bladder cancer (MIBC) who are circulating tumour (ct)DNA+ post cystectomy Ann Oncol 2021 32 S721 10.1016/j.annonc.2021.08.112
Powles TB, Gschwend JE, Bracarda S, Castellano D, Gross-Goupil M, Bjerggaard Jensen J et al (2021) 716TiP IMvigor011: a global, double-blind, randomised phase III study of atezolizumab (atezo; anti–PD-L1) vs placebo (pbo) as adjuvant therapy in patients (pts) with high-risk muscle-invasive bladder cancer (MIBC) who are circulating tumour (ct)DNA+ post cystectomy. Ann Oncol 32:S721. 10.1016/j.annonc.2021.08.112
35. Piatti P Chew YC Suwoto M Yamada T Jara B Jia XY Clinical evaluation of bladder CARE, a new epigenetic test for bladder cancer detection in urine samples Clin Epigenetics 2021 13 84 10.1186/s13148-021-01029-1 33882992
Piatti P, Chew YC, Suwoto M, Yamada T, Jara B, Jia XY et al (2021) Clinical evaluation of bladder CARE, a new epigenetic test for bladder cancer detection in urine samples. Clin Epigenetics 13:84. 10.1186/s13148-021-01029-133882992
36. Salari K Sundi D Lee JJ Wu S Wu CL DiFiore G Development and multicenter case-control validation of urinary comprehensive genomic profiling for urothelial carcinoma diagnosis, surveillance, and risk-prediction Clin Cancer Res 2023 29 3668 3680 10.1158/1078-0432.Ccr-23-0570 37439796
Salari K, Sundi D, Lee JJ, Wu S, Wu CL, DiFiore G et al (2023) Development and multicenter case-control validation of urinary comprehensive genomic profiling for urothelial carcinoma diagnosis, surveillance, and risk-prediction. Clin Cancer Res 29:3668–3680. 10.1158/1078-0432.Ccr-23-057037439796
37. Lotan Y SK, Feldman A, Sundi D, Lee J, DiFiore G, Poustchi H, Khoshnia M, Roshandel G, Etemadi A, Goudarzi M, Lentz PS, Phillips KG, Bicocca VT, Koppie TM, Gray JW, Levin T, Reza M, Sheikh M, Calvez-Kelm FL (2023) MP22-19 Urinary comprehensive genomic profiling predicts urothelial cancer up to 12 years ahead of clinical diagnosis An expanded analysis of the Golestan Cohort study. American Urological Society abstract. 209(suppl 4): e304. 10.1097/JU.0000000000003247.19
38. Meng W Efstathiou J Singh R McElroy J Volinia S Cui R MicroRNA biomarkers for patients with muscle-invasive bladder cancer undergoing selective bladder-sparing trimodality treatment Int J Radiat Oncol Biol Phys 2019 104 197 206 10.1016/j.ijrobp.2018.12.028 30583038
Meng W, Efstathiou J, Singh R, McElroy J, Volinia S, Cui R et al (2019) MicroRNA biomarkers for patients with muscle-invasive bladder cancer undergoing selective bladder-sparing trimodality treatment. Int J Radiat Oncol Biol Phys 104:197–206. 10.1016/j.ijrobp.2018.12.02830583038
39. Swinton M, Mariam NBG, Tan JL, Murphy K, Elumalai T, Soni M, et al. (2023) Bladder-sparing treatment with radical dose radiotherapy is an effective alternative to radical cystectomy in patients with clinically node-positive nonmetastatic bladder cancer. J Clin Oncol.41: 4406-4415. 10.1200/jco.23.00725
40. Sabaa MA El-Gamal OM Abo-Elenen M Khanam A Combined modality treatment with bladder preservation for muscle invasive bladder cancer Urol Oncol 2010 28 14 20 10.1016/j.urolonc.2008.07.005 18818110
Sabaa MA, El-Gamal OM, Abo-Elenen M, Khanam A (2010) Combined modality treatment with bladder preservation for muscle invasive bladder cancer. Urol Oncol 28:14–20. 10.1016/j.urolonc.2008.07.00518818110
41. Krasnow RE Drumm M Roberts HJ Niemierko A Wu CL Wu S Clinical outcomes of patients with histologic variants of urothelial cancer treated with trimodality bladder-sparing therapy Eur Urol 2017 72 54 60 10.1016/j.eururo.2016.12.002 28040351
Krasnow RE, Drumm M, Roberts HJ, Niemierko A, Wu CL, Wu S et al (2017) Clinical outcomes of patients with histologic variants of urothelial cancer treated with trimodality bladder-sparing therapy. Eur Urol 72:54–60. 10.1016/j.eururo.2016.12.00228040351
42. Barletta F, Tappero S, Panunzio A, Incesu RB, Cano Garcia C, Piccinelli ML, et al. (2022) Differences in cancer-specific mortality after trimodal therapy for T2N0M0 bladder cancer according to histological subtype. Cancers. 14: 5766. 10.3390/cancers14235766
43. Büchser D Zapatero A Rogado J Talaya M Martín de Vidales C Arellano R Long-term outcomes and patterns of failure following trimodality treatment with bladder preservation for invasive bladder cancer Urology 2019 124 183 190 10.1016/j.urology.2018.07.058 30266376
Büchser D, Zapatero A, Rogado J, Talaya M, Martín de Vidales C, Arellano R et al (2019) Long-term outcomes and patterns of failure following trimodality treatment with bladder preservation for invasive bladder cancer. Urology 124:183–190. 10.1016/j.urology.2018.07.05830266376
44. Alati A Fabiano E Geiss R Mareau A Charles-Nelson A Bibault JE Bladder preservation in older adults with muscle-invasive bladder cancer: a retrospective study with concurrent chemotherapy and twice-daily hypofractionated radiotherapy schedule J Geriatr Oncol 2022 13 978 986 10.1016/j.jgo.2022.05.014 35717533
Alati A, Fabiano E, Geiss R, Mareau A, Charles-Nelson A, Bibault JE et al (2022) Bladder preservation in older adults with muscle-invasive bladder cancer: a retrospective study with concurrent chemotherapy and twice-daily hypofractionated radiotherapy schedule. J Geriatr Oncol 13:978–986. 10.1016/j.jgo.2022.05.01435717533
45. Fabiano E, Durdux C, Dufour B, Mejean A, Thiounn N, Chrétien Y, et al. (2021) Long-term outcomes after bladder-preserving tri-modality therapy for patients with muscle-invasive bladder cancer. Acta Oncol (Stockholm, Sweden). 60: 794-802. 10.1080/0284186x.2021.1915498
46. Tunio MA Hashmi A Qayyum A Naimatullah N Mohsin R Sultan G Outcome of trimodality protocol for invasive bladder cancer patients at Karachi, Pakistan J Pak Med Assoc 2011 61 874 879 22360027
Tunio MA, Hashmi A, Qayyum A, Naimatullah N, Mohsin R, Sultan G (2011) Outcome of trimodality protocol for invasive bladder cancer patients at Karachi, Pakistan. J Pak Med Assoc 61:874–87922360027
47. Zietman AL Grocela J Zehr E Kaufman DS Young RH Althausen AF Selective bladder conservation using transurethral resection, chemotherapy, and radiation: management and consequences of Ta, T1, and Tis recurrence within the retained bladder Urology 2001 58 380 385 10.1016/s0090-4295(01)01219-5 11549485
Zietman AL, Grocela J, Zehr E, Kaufman DS, Young RH, Althausen AF et al (2001) Selective bladder conservation using transurethral resection, chemotherapy, and radiation: management and consequences of Ta, T1, and Tis recurrence within the retained bladder. Urology 58:380–385. 10.1016/s0090-4295(01)01219-511549485
48. Huddart RA Hall E Lewis R Porta N Crundwell M Jenkins PJ Patient-reported quality of life outcomes in patients treated for muscle-invasive bladder cancer with radiotherapy ± chemotherapy in the BC2001 Phase III Randomised Controlled Trial Eur Urol 2020 77 260 268 10.1016/j.eururo.2019.11.001 31843338
Huddart RA, Hall E, Lewis R, Porta N, Crundwell M, Jenkins PJ et al (2020) Patient-reported quality of life outcomes in patients treated for muscle-invasive bladder cancer with radiotherapy ± chemotherapy in the BC2001 Phase III Randomised Controlled Trial. Eur Urol 77:260–268. 10.1016/j.eururo.2019.11.00131843338
49. Zietman AL Sacco D Skowronski U Gomery P Kaufman DS Clark JA Organ conservation in invasive bladder cancer by transurethral resection, chemotherapy and radiation: results of a urodynamic and quality of life study on long-term survivors J Urol 2003 170 1772 1776 10.1097/01.ju.0000093721.23249.c3 14532773
Zietman AL, Sacco D, Skowronski U, Gomery P, Kaufman DS, Clark JA et al (2003) Organ conservation in invasive bladder cancer by transurethral resection, chemotherapy and radiation: results of a urodynamic and quality of life study on long-term survivors. J Urol 170:1772–1776. 10.1097/01.ju.0000093721.23249.c314532773
50. Katepratoom C Manchana T Amornwichet N Lower urinary tract dysfunction and quality of life in cervical cancer survivors after concurrent chemoradiation versus radical hysterectomy Int Urogynecol J 2014 25 91 96 10.1007/s00192-013-2151-6 23818129
Katepratoom C, Manchana T, Amornwichet N (2014) Lower urinary tract dysfunction and quality of life in cervical cancer survivors after concurrent chemoradiation versus radical hysterectomy. Int Urogynecol J 25:91–96. 10.1007/s00192-013-2151-623818129
51. Hyun J Ha MS Oh SY Tae JH Chi BH Chang IH Urinary tract infection after radiation therapy or radical prostatectomy on the prognosis of patients with prostate cancer: a population-based study BMC Cancer 2023 23 395 10.1186/s12885-023-10869-4 37138203
Hyun J, Ha MS, Oh SY, Tae JH, Chi BH, Chang IH et al (2023) Urinary tract infection after radiation therapy or radical prostatectomy on the prognosis of patients with prostate cancer: a population-based study. BMC Cancer 23:395. 10.1186/s12885-023-10869-437138203
52. Voskuilen CS van de Kamp MW Schuring N Mertens LS Noordzij A Pos F Radiation with concurrent radiosensitizing capecitabine tablets and single-dose mitomycin-C for muscle-invasive bladder cancer: a convenient alternative to 5-fluorouracil Radiother Oncol 2020 150 275 280 10.1016/j.radonc.2020.07.057 32768507
Voskuilen CS, van de Kamp MW, Schuring N, Mertens LS, Noordzij A, Pos F et al (2020) Radiation with concurrent radiosensitizing capecitabine tablets and single-dose mitomycin-C for muscle-invasive bladder cancer: a convenient alternative to 5-fluorouracil. Radiother Oncol 150:275–280. 10.1016/j.radonc.2020.07.05732768507
53. Lane JA Donovan JL Young GJ Davis M Walsh EI Avery KNL Functional and quality of life outcomes of localised prostate cancer treatments (Prostate Testing for Cancer and Treatment [ProtecT] study) BJU Int 2022 130 370 380 10.1111/bju.15739 35373443
Lane JA, Donovan JL, Young GJ, Davis M, Walsh EI, Avery KNL et al (2022) Functional and quality of life outcomes of localised prostate cancer treatments (Prostate Testing for Cancer and Treatment [ProtecT] study). BJU Int 130:370–380. 10.1111/bju.1573935373443
54. Zhang S Yu YH Zhang Y Qu W Li J Radiotherapy in muscle-invasive bladder cancer: the latest research progress and clinical application Am J Cancer Res 2015 5 854 868 25973322
Zhang S, Yu YH, Zhang Y, Qu W, Li J (2015) Radiotherapy in muscle-invasive bladder cancer: the latest research progress and clinical application. Am J Cancer Res 5:854–86825973322
55. Rastogi M Gandhi AK Tiwari R Nanda SS Rath S Khurana R Prospective evaluation of definitive chemoradiotherapy with volumetric modulated arc therapy in patients with muscle invasive carcinoma of urinary bladder Contemp Oncol (Pozn) 2020 24 177 182 10.5114/wo.2020.100275 33235544
Rastogi M, Gandhi AK, Tiwari R, Nanda SS, Rath S, Khurana R et al (2020) Prospective evaluation of definitive chemoradiotherapy with volumetric modulated arc therapy in patients with muscle invasive carcinoma of urinary bladder. Contemp Oncol (Pozn) 24:177–182. 10.5114/wo.2020.10027533235544
56. Huddart R, Hafeez S, Omar A, Alonzi R, Birtle A, Cheung KC, et al. (2023) Acute toxicity of hypofractionated and conventionally fractionated (Chemo)radiotherapy regimens for bladder cancer: an exploratory analysis from the RAIDER Trial. Clin Oncol (Royal College of Radiologists (Great Britain)). 35: 586-97. 10.1016/j.clon.2023.05.002
