Intravesical MMC has been a standard of care for the treatment of bladder cancer for over 30 years. As an extension of that use, physicians at various centers have also administered it intravesically at the onset of performing radical cystectomy or nephro-ureterectomy and then draining the bladder roughly 60 min later, prior to more formal bladder manipulation. This has been our standard clinical practice for more than 15 years and as such was incorporated into our standard operative consent. It was only later that we realized this practice was not uniformly applied elsewhere and, as such, we obtained appropriate IRB approval to perform this retrospective study.
In this study of 51 patients, intraoperative instillation of intravesical cytotoxic therapy at the time of nephroureterectomy was found to be safe. None of the patients experienced any adverse events directly attributable to MMC instillation either intraoperatively or postoperatively. This study provides safety data in support of a prospective trial designed to assess the efficacy of earlier intravesical chemotherapy in the prevention of bladder tumors after nephroureterectomy. Recent studies have found that without the administration of adjuvant postoperative intravesical therapy, the bladder urothelial carcinoma recurrence rate is approximately 25–70 % [10, 11] at median follow-up of 12–45 months. Two randomized studies have shown that in patients with upper tract urothelial carcinoma, postoperative intravesical instillation of a single dose of a cytotoxic agent such as MMC or THP decreases recurrence of bladder urothelial carcinoma. However, in these studies the intravesical cytotoxic agent was administered 2 days to a few weeks after the nephroureterectomy. The ODMIT-C trial was a multicenter phase III study that randomized 284 patients to MMC and control [10]. MMC was administered a median of 7 days after nephroureterectomy, at the time of catheter removal. At one year, there was a 10 % absolute and 40 % relative decrease in the risk of recurrence in the bladder with instillation of MMC. Ito et al. conducted a randomized phase II trial of single-dose intravesical instillation of THP that was administered within 48 h of surgery [11]. This trial randomized 77 patients and found an absolute decrease of 14.9 % and 25.3 % at one and two years, respectively. Interestingly, in both studies the absolute incidence of bladder tumors in the treatment arm was about 16 %, with a number needed to treat of 9 in the ODMIT trial. For patients with bladder urothelial carcinoma, studies have shown the instillation of MMC reduces recurrence rates when administered within 6 h of surgery, but not when it is instilled greater than 24 h after surgery [23–25]. In fact, one randomized controlled trial demonstrated that pre-TURBT electromotive instillation of MMC was superior to post-TURBT MMC. [26].
Hence, it is entirely plausible that the efficacy of MMC in preventing recurrence of the urothelial carcinoma in the bladder may be higher if MMC is administered during or immediately after nephroureterectomy rather than several days later.
Immediate postoperative instillation of MMC in the bladder after TURBT has been shown to be safe even in the setting of tumor resection and some element of continued bleeding, so it is not surprising that our experience with instillation and immediate drainage was not associated with any adverse effects.
In the ODMIT-C trial, the timing of instillation was delayed due to concern for extravasation of MMC into the pelvis from the bladder [10]. Within the THP monotherapy study group trial, administration of intravesical chemotherapy was within 48 h of surgery [11]. The group did not mention the reason for choosing this particular time for instillation, but did note that the bladder cuff resection was performed in an open fashion so as to assure the wall was tightly sutured. In theory, this timing of administration might have decreased the efficacy of these agents.
Despite evidence from these 2 randomized studies [10], postoperative intravesical instillation of MMC at the time of catheter removal has not become standard practice. The reasons for this lack of dissemination and implementation are not known and are likely multi-factorial. Even after TURBT, when safety and efficacy rates are known to be high, the utilization of a single postoperative dose of mitomycin has been reported to be as low as 38 % [27]. One contributing factor may be that intravesical instillation is not built into the workflow of the typical postoperative course, and in many cases may require the patient to return to the clinic after hospital discharge. When patients return for follow-up and catheter removal, the clinic encounter is likely to be focused on the patient’s symptoms and discussion of the pathology report, prognosis and treatment plan. Additional barriers such as the need for timely coordination with the pharmacy, biohazard precautions and the requirement for specialized nursing may make the administration of MMC less likely. Therefore, it is plausible that by standardizing the administration of MMC intraoperatively and engaging the urologic team directly, it may increase the probability of patients receiving this therapy.
At our institution, a number of physicians (8 over the last 12 years) have instilled cytotoxic chemotherapy in the bladder at the time of nephroureterectomy. To the best of our knowledge, we are the first to report on the safety of this approach. Our experience with 51 patients has been a highly positive one. All patients tolerated the instillation without issue and no intra or postoperative complications related to cytotoxic chemotherapy occurred. A larger prospective study would provide greater reliability on the safety of this approach as well as more reliable data in regard to its efficacy, which theoretically could be better than the previously described randomized studies.
There are number of limitations that should be addressed. Our review included data from 51 patients who underwent nephroureterectomy from 2000 to 2012 and included 28 patients who had a prior history of bladder cancer. As such, time to recurrence of bladder cancer is not meaningful and efficacy cannot be studied in this cohort. Additionally, a retrospective review of complications may underestimate the number of complications that occurred; however, our data are comparable to a number of previous reports and highlight the relatively low but significant percentage of Clavien grades 3 and 4 complications. Second, the handling of the distal ureter was left to the discretion of the surgereon, though the majority of cases (30/51) involved an extravesical excision of the ureter along with a bladder cuff. Next, there are currently no data on the efficacy of intraoperative intravesical cytotoxic chemotherapy for upper tract urothelial carcinoma, though extrapolation from TURBT data may be appropriate. This does, however, highlight an important reminder from our study – the rarity of upper tract urothelial carcinoma and the inherent difficulty in studying a rare disease. The majority of our patients had a prior history of bladder cancer, whereas to study the efficacy of an intravesical agent, a cohort of patients without prior bladder cancer is needed. Thus, given the rarity of the disease, and our findings demonstrating that intraoperative instillation of intravesical cytotoxic chemotherapy is safe, multicenter prospective trials are needed to determine whether this approach is effective in preventing recurrence of urothelial carcinoma in the bladder following nephroureterectomy. This data provides important preliminary safety data in support of such a trial.
