Editorial by Stephen A. Boorjian on pp. 711–712 of this issue
Prevention of Bladder Tumours after Nephroureterectomy for Primary Upper Urinary Tract Urothelial Carcinoma: A Prospective, Multicentre, Randomised Clinical Trial of a Single Postoperative Intravesical Dose of Mitomycin C (the ODMIT-C Trial)☆
To prevent bladder tumour after nephroureterectomy with a single postoperative dose of intravesical mitomycin C (MMC).
Design, setting, and participants
A prospective, randomised, nonblinded trial (ODMIT-C: One Dose Mitomycin C) was undertaken in 46 British centres between July 2000 and December 2006. The study recruited 284 patients with no previous or concurrent history of bladder cancer undergoing nephroureterectomy for suspected UUTUC.
Intervention
A single postoperative intravesical dose of MMC (40 mg in 40 ml saline) or standard management on removal of the urinary catheter.
Measurements
Bladder tumour formation was judged by visual appearance at cystoscopy at 3, 6, and 12 mo following nephroureterectomy.
Results and limitations
One hundred forty-four patients were randomised to receive MMC and 140 patients to receive standard care. In the MMC arm, 105 of 144 patients (73%) and 115 of 140 patients (82%) in the standard care arm received their allocated treatment. Thirteen of 105 patients who received MMC and 20 of 115 patients allocated to standard treatment did not complete follow-up. By modified intention-to-treat analysis, 21 of 120 patients (17%) in the MMC arm developed a bladder recurrence in the first year compared to 32 of 119 patients (27%) in the standard treatment arm (p = 0.055). By treatment as per protocol analysis, 17 of 105 patients (16%) in the MMC arm and 31 of 115 patients (27%) in the standard treatment arm developed a recurrence (p = 0.03). No serious adverse events were reported. A limitation is that histologic proof of recurrence was not required in this trial.
Conclusions
A single postoperative dose of intravesical MMC appears to reduce the risk of a bladder tumour within the first year following nephroureterectomy for UUTUC. The absolute reduction in risk is 11%, the relative reduction in risk is 40%, and the number needed to treat to prevent one bladder tumour is nine.
Introduction
Approximately 10% of kidney tumours arise primarily in the renal pelvis or ureter and are termed upper urinary tract urothelial carcinomas (UUTUC). Annually, around 800 people per year in the United Kingdom and 6300 people in the European Union will be diagnosed with UUTUC [1]. Standard management of UUTUC is nephroureterectomy [2], but after a nephroureterectomy, up to 40% of patients will develop bladder cancer (BCa) [3], [4]. In this population, a reduction in the need for subsequent bladder tumour surgery is inherently desirable and theoretically could reduce the risk of subsequent seeding into the contralateral ureter, reduce the risk of renal failure from tumour or from damage to the contralateral ureteric orifice during bladder tumour surgery, possibly reduce the risk of tumour progression, and reduce the overall costs of treatment.
The pathogenesis of BCa arising following previous UUTUC is controversial. Theoretically, tumours could result from a field effect, or they could be implantation metastases resulting from seeding from the UUTUC. Molecular and clinical evidence suggests that seeding is a possible factor. The molecular evidence comes from studies demonstrating that UUTUC and BCa are often monoclonal [5], [6]. These findings were a logical extension of Sidransky's work, which demonstrated that multifocal bladder tumours could be monoclonal and therefore were likely to be implantation metastases [7].
The clinical evidence supporting implantation metastasis of UUTUC is threefold: first, around 70% of BCa cases that develop following nephroureterectomy do so in the first year following surgery [3]; second, the incidence of BCa following a diagnosis of UUTUC is about 35%, whereas the incidence of UUTUC following a bladder tumour is around 5% [3]; third, a single dose of intravesical chemotherapy following transurethral resection of a bladder tumour (TURBT) reduces recurrence from around 40% to 26% [8], [9], [10]. Intravesical chemotherapy has not been tested in randomised trials in attempts to reduce the incidence of BCa after treatment of UUTUC. Data from Taiwan from a nonrandomised study suggest that six doses of intravesical chemotherapy, given weekly following nephroureterectomy, does not reduce the incidence of BCa but might delay the time to recurrence [4]. We surmised that administration of a single dose of intravesical chemotherapy in the early postoperative period after nephroureterectomy for UUTUC might prevent successful seeding of transitional cancer cells and therefore might help reduce the incidence of BCa in the first year post surgery.
Section snippets
Study design and enrolment
A multicentre randomised trial design was proposed to the executive of the British Association of Urological Surgeons Section of Oncology in 2000. Multicentre research ethics approval was obtained, and the trial was approved as part of the National Cancer Research Network trials portfolio. The trial protocol is available online (www.sxrc.nhs.uk/consortium_activity/study0062.htm). The trial was registered in the International Standard Randomised Controlled Trial Number Register under ISRCTN
Results
Two hundred eighty-four patients were randomised between 20 July 2000 and 27 December 2006. The characteristics of the patients and tumours are shown in Table 1. The groups were well matched for age and multifocality of tumour. There were more high-grade tumours in the MMC-treated arm (n = 50) than in the standard treatment arm (n = 42). The flow of the patients through the study is summarised in the Consolidated Standards of Reporting Trials flow diagram (Fig. 1) [11]. The methods of
Discussion
This trial is the largest randomised trial ever performed on the management of patients with UUTUC. It has shown that a single dose of intravesical MMC at the time of urethral catheter removal following nephroureterectomy can reduce the risk of developing a bladder tumour in the subsequent year by almost 40%, with little risk of an adverse event.
The mechanism of action of MMC is possibly to reduce successful seeding of cells shed from the UUTUC. The milieu in the bladder at the time of
Conclusions
ODMIT-C is the largest randomised trial ever performed in the management of patients with UUTUC. A single dose of intravesical MMC following nephroureterectomy appears to reduce the risk of developing a bladder tumour in the subsequent year, with a low risk of complications. The absolute reduction in risk is 11%, the relative risk reduction is 40%, and the number needed to treat to prevent one bladder tumour is nine.
The European Association of Urology (EAU) guidelines panel on upper urinary tract urothelial carcinoma (UTUC) has updated the guidelines to aid clinicians in evidence-based management of UTUC.
To provide an overview of the EAU guidelines on UTUC as an aid to clinicians.
The recommendations provided in these guidelines are based on a review of the literature via a systematic search of the PubMed, Ovid, EMBASE, and Cochrane databases. Data were searched using the following keywords: urinary tract cancer, urothelial carcinomas, renal pelvis, ureter, bladder cancer, chemotherapy, ureteroscopy, nephroureterectomy, neoplasm, (neo)adjuvant treatment, instillation, recurrence, risk factors, metastatic, immunotherapy, and survival. The results were assessed by a panel of experts.
Even though data are accruing, for many areas there is still insufficient high-level evidence to provide strong recommendations. Patient stratification on the basis of histology and clinical examination (including imaging) and assessment of patients at risk of Lynch syndrome will aid management. Kidney-sparing management should be offered as a primary treatment option to patients with low-risk UTUC and two functional kidneys. In particular, for patients with high-risk or metastatic UTUC, new treatment options have become available. In high-risk UTUC, platinum-based chemotherapy after radical nephroureterectomy, and adjuvant nivolumab for unfit or patients who decline chemotherapy, are options. For metastatic disease, gemcitabine/carboplatin chemotherapy is recommended as first-line treatment for cisplatin-ineligible patients. Patients with PD-1/PD-L1–positive tumours should be offered a checkpoint inhibitor (pembrolizumab or atezolizumab).
These guidelines contain information on the management of individual patients according to the current best evidence. Urologists should take into account the specific clinical characteristics of each patient when determining the optimal treatment regimen according to the risk stratification of these tumours.
Cancer of the upper urinary tract is rare, but because 60% of these tumours are invasive at diagnosis, timely and appropriate diagnosis is most important. A number of known risk factors exist.
Bladder recurrences have been reported in 22–47% of patients after surgery for upper urinary tract urothelial carcinoma (UTUC). This collaborative review focuses on risk factors for and treatment strategies to reduce bladder recurrences after upper tract surgery for UTUC.
To review the current evidence on risk factors and treatment strategies for intravesical recurrence (IVR) after upper tract surgery for UTUC.
This collaborative review is based on a literature search of PubMed/Medline, Embase, Cochrane Library, and currently available guidelines on UTUC. Relevant papers on bladder recurrence (etiology, risk factors, and management) after upper tract surgery were selected. Special attention has been paid to (1) the genetic background of bladder recurrences, (2) bladder recurrences after ureterorenoscopy (URS) with or without a biopsy, and (3) postoperative or adjuvant intravesical instillations. The literature search was performed in September 2022.
Recent evidence supports the hypothesis that bladder recurrences after upper tract surgery for UTUC are often clonally related. Clinicopathologic risk factors (patient, tumor, and treatment related) have been identified for bladder recurrences after UTUC diagnosis. Specifically, the use of diagnostic ureteroscopy before radical nephroureterectomy (RNU) is associated with an increased risk of bladder recurrences. Further, a recent retrospective study suggests that performing a biopsy during ureteroscopy may further worsen IVR (no URS: 15.0%; URS without biopsy: 18.4%; URS with biopsy: 21.9%). Meanwhile, a single postoperative instillation of intravesical chemotherapy has been shown to be associated with a reduced bladder recurrence risk after RNU compared with no instillation (hazard ratio 0.51, 95% confidence interval 0.32–0.82). Currently, there are no data on the value of a single postoperative intravesical instillation after ureteroscopy.
Although based on limited retrospective data, performing URS seems to be associated with a higher risk of bladder recurrences. Future studies are warranted to assess the influence of other surgical factors as well as the role of URS biopsy or immediate postoperative intravesical chemotherapy after URS for UTUC.
In this paper, we review recent findings on bladder recurrences after upper tract surgery for upper urinary tract urothelial carcinoma.
The aim was to propose an update of the French Urology Association Cancer Committee (ccAFU) Recommendations on the management of upper urinary tract urothelial carcinomas (UUT-UC).
A systematic Medline search was performed between 2020 and 2022, taking account of the diagnosis, treatment options and follow-up of UUT-UC, while evaluating the references with their levels of evidence.
The diagnosis of this rare pathology is based on CTU acquisition during excretion and flexible ureterorenoscopy with histological biopsies. Radical nephroureterectomy (RNU) remains the gold standard for surgical treatment. Nevertheless conservative treatment can be discussed for low risk lesions: tumour of low-grade, with no infiltration on imaging, unifocal < 2 cm, eligible for full treatment therefore requiring close endoscopic surveillance by flexible ureteroscopy in compliant patients. After RNU, postoperative instillation of chemotherapy is recommended to reduce the risk of recurrence in the bladder. Adjuvant chemotherapy has shown clinical benefits compared to surveillance after RNU for tumours (pT2-T4 N0-3 M0).
These updated recommendations should contribute to improving not only patients’ level of care, but also the diagnosis and decision-making concerning treatment for UUT-UC.
L’objectif était de proposer une mise à jour des recommandations du Comité de Cancérologie de l’Association française d’urologie pour la prise en charge des tumeurs de la voie excrétrice supérieure (TVES).
Une revue systématique de la littérature (Medline) a été effectuée de 2020 à 2022 sur les éléments du diagnostic, les options de traitement et la surveillance des TVES en évaluant les références avec leur niveau de preuve.
Le diagnostic de cette pathologie rare repose sur l’uro-TDM avec acquisition au temps excréteur et l’urétérorénoscopie souple avec prélèvements biopsiques. Le traitement chirurgical de référence est la néphrourétérectomie totale (NUT), mais un traitement conservateur peut être discuté pour les lésions dites à bas risque : tumeur de bas grade, sans d’infiltration sur l’imagerie, unifocale < 2 cm, accessible à un traitement complet et nécessitant alors une surveillance endoscopique rapprochée par urétéroscopie souple chez un patient compliant. Une instillation postopératoire de chimiothérapie est recommandée et permet de diminuer le risque de récidive vésicale après NUT. La chimiothérapie adjuvante a démontré son bénéfice clinique comparée à la surveillance après NUT pour les tumeurs (pT2-T4 N0-3 M0).
Ces nouvelles recommandations doivent contribuer à améliorer non seulement la prise en charge des patients, mais aussi le diagnostic et la décision thérapeutique des TVES.
