(UroToday.com) The 2023 EAU annual meeting included an EAU guideline session on effective treatment in upper tract urothelial tumors, featuring a debate discussing whether it is possible to consider systematic immediate intravesical instillation after radical nephroureterectomy.
Dr. Francesco Soria started with two case presentations, the first a 70 year old male, active smoker with comorbidities including COPD. In August 2021, he underwent a left ureteroscopy + biopsy + incomplete Holmium laser ablation of a left upper tract tumor, for which the tumor was deemed not endoscopically manageable:
In October 2021, he subsequently underwent a left retroperitoneal robotic nephroureterectomy with bladder cuff closure, and pathology pTa low grade upper tract urothelial carcinoma. The second case was a 67 year old male, former smoker with no significant comorbidities who in January 2022 had right renal colic, with ultrasound suggesting hydronephrosis, and subsequent CT scan showing a right 3 cm ureteral tumor:
In March 2022, he subsequently underwent a right retroperitoneal robotic nephroureterectomy with bladder cuff closure (pathology not listed). The post-operative day 5 cystogram for patient 1 showed no leak, however for patient 2 showed a significant posterior bladder leak.
Pro Position
The pro position for systematic immediate intravesical instillation of chemotherapy after nephroureterectomy was taken by Dr. Albert Martini. The reason for postoperative instillation is because of the high risk of bladder cancer recurrence after radical nephroureterectomy, particularly among patients with a previous history of bladder cancer:
Work from Dr. Martini’s group [1] suggests that at 5 years, the time point after which cystoscopies should be performed semiannually, the bladder recurrence risk is 10%; at 4 years, the bladder recurrence risk is 13%. At 2 years after radical nephroureterectomy, the time point after which imaging should be obtained semiannually, the nonbladder recurrence risk is 42% in case of nonprior bladder cancer and 47% in cases of prior bladder cancer. In a Cochrane review of two prospective clinical trials, a single-dose of intravesical chemotherapy instillation may reduce the risk of bladder cancer recurrence over time compared to no instillation, with a HR of 0.51 (95% CI 0.32 to 0.82).
Historical studies suggest a clonal origin of bladder cancer. In a study of 29 patients with upper tract urothelial carcinoma and a history of a subsequent bladder urothelial carcinoma, the risk of bladder recurrence after upper tract urothelial carcinoma was significantly associated with mutations in FGFR3, KDM6A, CCND1, and TP53 [2]. Comparison of bladder urothelial carcinoma with corresponding upper tract urothelial carcinoma tumors from the same patient supports their clonal relatedness:
With regards to the EAU guidelines, Dr. Martini notes that the level of evidence is 1B for a single post-operative intravesical instillation of chemotherapy lowering the bladder cancer recurrence rate, and there is a strong recommendation for delivering a post-operative bladder instillation of chemotherapy to lower the intravesical recurrence rate. Dr. Martini concluded his portion of the debate with the following messages:
- Bladder recurrence following radical nephroureterectomy is high, and higher in cases of a prior history of bladder cancer
- Recurrence is mostly clonal
- Early post-operative instillations have been evaluated in prospective trials and meta-analyses
- Complications after a single post-operative dose are extremely rare
Future directions include the potential use of gene therapy (ie. nadofaragene firadenovec) as a single post-operative dose.
Con Position
The con position for systematic immediate intravesical instillation of chemotherapy after nephroureterectomy was taken by Dr. Alexandra Masson-Lecomte. She started by emphasizing that the clinical trials supporting a single post-operative dose of chemotherapy is weak, and insufficient to recommend it systematically. The first trial was the ODMIT-C trial [3], which was a prospective, randomized, nonblinded trial in 46 British centers between July 2000 and December 2006 that recruited 284 patients with no previous or concurrent history of bladder cancer undergoing nephroureterectomy for suspected upper tract urothelial carcinoma. Patients were randomized to a single postoperative intravesical dose of 40 mg mitomycin C or standard management on removal of the urinary catheter. By modified intention-to-treat analysis, 21 of 120 patients (17%) in the mitomycin C 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 mitomycin C arm and 31 of 115 patients (27%) in the standard treatment arm developed a recurrence (p = 0.03). Dr. Masson-Lecomte notes several issues with this trial:
- There was a large sample size, but unbalanced for stage
- There was no histological proof of recurrence needed, leading to detection bias
- It was unblinded, leading to performance bias
- The sample size calculation was based on an over-optimistic relative reduction of recurrence risk (50%)
- This was a negative trial in the intention to treat population (p = 0.055)
The second trial enrolled 77 patients that were randomly assigned to receive or not receive a single instillation of 30 mg pirarubicin in the bladder within 48 hours after nephroureterectomy. Overall 72 patients were evaluable for the efficacy analysis, 21 of whom had a subsequent bladder recurrence. Significantly fewer patients who received pirarubicin had a recurrence compared with the control group (16.9% at 1 year and 16.9% at 2 years in the pirarubicin group vs 31.8% at 1 year and 42.2% at 2 years in the control group; log-rank p= 0.025). Dr. Masson-Lecomte notes several issues with this trial:
- The sample size was calculated assuming a huge difference in recurrence rates between the groups (9% vs 43%)
- The study was underpowered
- There was imbalance for grade of disease, which is a factor associated with bladder recurrence
The second point from Dr. Masson-Lecomte was that indeed complications are rare, but could be lethal if they occur. Although somewhat under-reported, Dr. Masson-Lecomte notes there are reports of acute and chronic pain, persistent leak, ureteral obstruction, cellulitis, severe lower urinary tract symptoms, intestinal obstruction, and death after a single post-operative instillation. Dr. Masson-Lecomte argues that we should probably not be systematically treating patients, but rather take a tailored approached according to risk of bladder recurrence. These risk factors include:
- Patient specific: male, smoking, chronic kidney disease
- Tumor specific: cytology, grade, ureteral location, multifocality, pT stage, necrosis
- Treatment specific: laparoscopic approach, extravesical bladder cuff removal, positive surgical margins
Additionally, other options should be explored, including intraoperative and preoperative instillations:
Dr. Masson-Lecomte concluded her portion of the debate with the following concluding remarks:
- Evidence for a single post-operative dose of chemotherapy is weak
- The consequences may be devastating
- Do not perform post-operative instillation if you have any doubt about bladder cuff leakage potential
- Inform the patient about benefit and risk
- Tailored treatment should be the goal
- Pre or peri operative instillations could be the safest option, but still need to be investigated
Presented by: Francesco Soria, San Giovanni Battista Hospital, University of Turin, Turin, Italy
Pro Position Presented by: Alberto Martini, The University of Texas MD Anderson Cancer Center, Houston, Texas
Con Position Presented by: Alexandra Masson-Lecomte, Saint Louis Hospital, Paris Cite University, Paris, France
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2023 European Association of Urology (EAU) 38th annual congress held in Milan, Italy between March 10-13, 2023
References:
- Martini A, Lonati C, Nocera L, et al. Oncologic Surveillance after Radical Nephroureterectomy for High-Risk Upper Tract Urothelial Carcinoma. Eur Urol Oncol. 2022 Aug;5(4):451-459.
- Audenet F, Isharwal S, Cha EK, et al. Clonal relatedness and mutational differences between upper tract and bladder urothelial carcinoma. Clin Cancer Res. 2019 Feb 1;25(3):967-976.
- O’Brien T, Ray E, Singh R, et al. Prevention of bladder tumours after nephroureterectomy for primary upper urinary tract urothelial carcinoma: A prospective, multicentre, randomized clinical trial of a single postoperative intravesical dose of mitomycin C (the ODMIT-C Trial). Eur Urol 2011 Oct;60(4):703-710.
- Ito A, Shintaku I, Satoh M, et al. Prospective randomized phase II trial of a single early intravesical instillation of pirarubicin (THP) in the prevention of bladder recurrence after nephroureterectomy for upper urinary tract urothelial carcinoma: the THP Monotherapy Study Group Trial. J Clin Oncol 2013 Apr 10;31(11):1422-1427.