Review article
Endocavitary treatment for upper tract urothelial carcinoma: A meta-analysis of the current literature

https://doi.org/10.1016/j.urolonc.2019.02.004Get rights and content

Highlights

  • The pooled estimates for patients with superficial upper tract urothelial carcinoma who underwent endoscopic laser ablation followed by adjuvant instillation therapy were 40% for upper tract recurrence, 94% for cancer-specific survival, and 71% for overall survival.

  • The pooled effect sizes for patients with upper tract carcinoma in situ treated with BCG instillation therapy were 84%, 34%, and 16% for cytology response, upper tract recurrence, and progression, respectively.

  • Comparisons between different drug regimens as well as instillation approaches did not show significant differences.

  • While the efficacy of endocavitary upper tract instillations in superficial upper tract urothelial carcinoma remains to be demonstrated, upcoming novel drugs and instillation approaches have to challenge these results.

Abstract

Purpose: To assess the oncologic impact of adjuvant endocavitary instillation after kidney-sparing surgery (KSS) in the treatment of upper tract urothelial carcinoma (UTUC). Methods: A meta-analysis of the available literature was performed using PUBMED and MEDLINE on June 2018. No time or language restrictions were applied. All included participants were substratified into 2 groups: Ta/T1 UTUC and upper tract (UT) carcinoma in situ. Subjects with higher stage disease, involvement of the bladder, or urethra were excluded. Predefined endpoints of interest were rates of cytology response, UT recurrence, UT progression, cancer-specific survival, and overall survival. Results: Overall, 27 eligible reports for a total of 438 patients were identified and 18 studies included for quantitative analyses. All included reports were nonrandomized observational case series. Among studies that reported on UT recurrence, 154 (35%) patients developed UT recurrence during a median follow-up of 30 months. The overall pooled estimates for adjuvant instillations in Ta-T1 patients were 40% for UT recurrence, 94% for cancer-specific survival, and 71% for OS. Subanalyses stratified by regimen used and instillation approach did not show any significant differences. In patients with UT carcinoma in situ treated with BCG, the pooled estimates for cytology response, UT recurrence, and progression were 84%, 34%, and 16%, respectively. Similarly, comparison between instillation approaches did not show any significant differences. Conclusions: In this meta-analysis of presumed nonmuscle invasive patients treated with kidney-sparing surgery, endocavitary instillations for noninvasive UTUC, did not reveal any differences between the regimens and instillations approaches. Patients with Ta-T1 UTUC had an UT recurrence rate comparable to that reported in the literature for nontreated patients. To date, the efficacy of endocavitary instillations in UTUC remains to be demonstrated. Upcoming novel drugs promise to change this paradigm.

Introduction

Upper tract urothelial carcinoma (UTUC) accounts for 5% of all urothelial cancers, with an estimated annual incidence of 1 to 2 cases per 100,000 [1]. UTUC exhibits aggressive clinical behavior with 5-year cancer-specific survival (CSS) rates varying from 10% to 70%, mainly depending on tumor stage and lymph-nodal status at diagnosis [2], [3], [4], [5]. To date, the standard treatment for nonmetastatic UTUC remains radical nephro-ureterectomy with bladder cuff excision. At some centers, perioperative cisplatin-based combination chemotherapy is administered followed by surgery with lymphadenectomy [6]. In recent years, a kidney-sparing approach to UTUC patients has become more acceptable with the aim of preserving renal function and preventing the long-term complications associated with chronic kidney disease, without compromising oncologic outcomes and surgical safety [7], [8]. To date, kidney-sparing surgery (KSS) is indicated in patients harboring a tumor size ≤2 cm, unifocal disease, low-grade cytology, low-grade cancer on ureteroscopic biopsy, and no evidence of invasion or extra-organ spread on computer tomography [6], [9], [10], [11], [12], [13].

In patients treated with KSS, recurrence in the upper and lower urinary tract is quite common, affecting 15% to 90% of patients, depending on the case mix and follow-up [14], [15]. Therefore, similar to the management of nonmuscle invasive bladder cancer (NMIBC), adjuvant endocavitary instillations have been proposed in patients treated with KSS, with the aim of reducing recurrence and progression rates in low risk papillary UTUCs and to treat upper tract (UT) carcinoma in situ (CIS); however, adjuvant endocavitary treatment is not routinely recommended by any national or international guidelines [6]. The evidence supporting the use of endocavitary instillations is scarce and mainly consists of small, single-center series, characterized by a relatively short follow-up, retrospective study design and the problems associated with reporting bias [16]. The widespread use of adjuvant instillations after KSS has been limited by concerns regarding the method of administration and the unsatisfactory oncologic results. The major challenge of adjuvant endocavitary treatment resides in specific anatomic and physiologic characteristics of the upper urinary tract which has no storage capacity and is bathes continuously by the downward flow of urine produced by the kidneys [14].

To overcome these limitations, novel methods such as slow-release formulations including stents and hydrogel polymers with reverse-thermal gelation properties (liquid at cold temperature and soft, adherent gel at body temperature) and mitomycin C (MMC) have been developed and tested in preclinical models [17], [18], [19]. The aim of this review and meta-analysis was to investigate the oncologic efficacy of endocavitary therapies for the treatment of UTUC to create an up-to-date reference point for comparison to these new methods of drug delivery. The primary endpoints of our study were endocavitary recurrence, progression, and mortality. Bladder recurrence was not assessed in this study.

Section snippets

Study eligibility

This meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement [20]. The literature search was performed nonsystematically by 2 authors to identify studies investigating UT instillation therapies in UTUC patients. We searched PubMed and MEDLINE in June 2018 using the following string terms: (“UTUC” OR “urothelial carcinoma” OR “upper tract” OR “upper urinary tract”) AND (“instillation” OR “instillation therapy” OR “intracavitary

Results

We identified 27 eligible reports and included 18 studies for quantitative analyses. All included reports were nonrandomized observational analyses or case series with sample sizes ranging from 5 to 50 patients. All selected studies comprised a total of 438 participants who received UT instillation therapy for Ta, T1, or Tis UTUC. Among studies that reported on UT recurrence, 154 (35%) patients developed UT recurrence during a median follow-up of 30 months.

Discussion

In this pooled analysis, we investigated the oncologic outcomes (excluded bladder recurrence) of patients with papillary UTUC or CIS of the UT treated with KSS and adjuvant endocavitary treatment. We separately analyzed the therapeutic effect of adjuvant therapies (i.e., chemotherapeutic agents and/or immunotherapy with BCG) after KSS for papillary noninvasive (Ta-T1) UTUCs and of adjuvant BCG for the treatment of UT CIS.

We found no difference between the way of drug administration (antegrade

Conclusions

In this meta-analysis, we investigated the oncological outcomes of patients with noninvasive UTUC treated with endocavitary instillations. We found no differences between the type of drug used (MMC vs. BCG) for the adjuvant treatment of patients with Ta-T1 UTUC in terms of RFS, CSS, and OS. Moreover, both in patients with Ta-T1 UTUC and in those treated with BCG for UT CIS, no differences were found with regards to the type of approach used for instillations (antegrade vs. retrograde). Finally,

References (54)

  • A.A. Barros et al.

    Drug-eluting biodegradable ureteral stent: new approach for urothelial tumors of upper urinary tract cancer

    Int J Pharm

    (2016)
  • R. DerSimonian et al.

    Meta-analysis in clinical trials

    Control Clin Trials

    (1986)
  • M.P. Schoenberg et al.

    The management of transitional cell carcinoma in solitary renal units

    J Urol

    (1991)
  • J.A. Eastham et al.

    Technique of mitomycin C instillation in the treatment of upper urinary tract urothelial tumors

    J Urol

    (1993)
  • J.A. Martínez-Piñeiro et al.

    Endourological treatment of upper tract urothelial carcinomas: analysis of a series of 59 tumors

    J Urol

    (1996)
  • F.X. Keeley et al.

    Adjuvant mitomycin C following endoscopic treatment of upper tract transitional cell carcinoma

    J Urol

    (1997)
  • A. Patel et al.

    New techniques for the administration of topical adjuvant therapy after endoscopic ablation of upper urinary tract transitional cell carcinoma

    J Urol

    (1998)
  • M.C. Goel et al.

    Percutaneous management of renal pelvic urothelial tumors: long-term followup

    J Urol

    (2003)
  • J. Palou et al.

    Percutaneous nephroscopic management of upper urinary tract transitional cell carcinoma: recurrence and long-term followup

    J Urol

    (2004)
  • G. Giannarini et al.

    Antegrade perfusion with bacillus Calmette-Guérin in patients with non-muscle-invasive urothelial carcinoma of the upper urinary tract: who may benefit?

    Eur Urol

    (2011)
  • J.R. Sharpe et al.

    Intrarenal bacillus Calmette-Guerin therapy for upper urinary tract carcinoma in situ

    J Urol

    (1993)
  • A. Irie et al.

    Intravesical instillation of bacille Calmette-Guérin for carcinoma in situ of the urothelium involving the upper urinary tract using vesicoureteral reflux created by a double-pigtail catheter

    Urology

    (2002)
  • G.N. Thalmann et al.

    Long-term experience with bacillus Calmette-Guerin therapy of upper urinary tract transitional cell carcinoma in patients not eligible for surgery

    J Urol

    (2002)
  • Y. Hayashida et al.

    Long-term effects of bacille calmette-guérin perfusion therapy for treatment of transitional cell carcinoma in situ of upper urinary tract

    Urology

    (2004)
  • U.E. Studer et al.

    Percutaneous bacillus Calmette-Guerin perfusion of the upper urinary tract for carcinoma in situ

    J Urol

    (1989)
  • O. Yossepowitch et al.

    Assessment of vesicoureteral reflux in patients with self-retaining ureteral stents: implications for upper urinary tract instillation

    J Urol

    (2005)
  • N. Kleinmann et al.

    LBA25 non-surgical management of low grade upper tract urothelial cancer: an interim analysis of the International Multicenter Olympus Trial (NCT02793128)

    J Urol

    (2018)
  • Cited by (45)

    • Topical instillation of BCG immunotherapy for biopsy-proven primary upper urinary tract carcinoma in situ: A single institution series and systematic review

      2023, Urologic Oncology: Seminars and Original Investigations
      Citation Excerpt :

      The chosen approach depends mainly on patients’ characteristics and on clinics’ preference. Some studies have compared complications and oncological outcomes between each approach and found similar results [14,24]. Although D-J stent was the most frequent approach used, it should be emphasized that D-J seems to be a not homogeneous vehicle UUT BCG instillations.

    • Is iodine-125 seed strand brachytherapy suitable for ureteral carcinoma?

      2022, Urologic Oncology: Seminars and Original Investigations
    • French AFU Cancer Committee Guidelines – Update 2022–2024: Upper urinary tract urothelial cancer (UTUC)

      2022, Progres en Urologie
      Citation Excerpt :

      Le reflux vésico-urétéral obtenu par une sonde JJ a également été décrit mais n’est pas reproductible chez tous les patients [86]. L‘efficacité de ces instillations reste à démontrer [87]. Un essai prospectif non randomisé a évalué l’efficacité d’une instillation adjuvante unique de Mitomycine C immédiatement après traitement conservateur pour TVES de bas grade.

    • Novel Classification for Upper Tract Urothelial Carcinoma to Better Risk-stratify Patients Eligible for Kidney-sparing Strategies: An International Collaborative Study

      2022, European Urology Focus
      Citation Excerpt :

      For example, patients deemed at high risk because of two small low-grade tumors may benefit from endoscopic resection, as new technologies have improved our ability to detect and treat larger or multiple UTUC tumors via endoscopy [4–7]. In addition, this subset of patients with multiple low-grade tumors probably represent ideal candidates for further adjuvant UT instillations [8–10]. UT instillations are not clearly recommended, in part because of the absence of a risk stratification that can better identify patients who are at risk of recurrence.

    View all citing articles on Scopus
    View full text