Currently, the disease management of patients with IVR after radical nephroureterectomy (RNU) for UTUC (UTUC-BC) is based on the primary BC guidelines. For non-muscle invasive bladder cancer (NMIBC), the transurethral resection of bladder tumor (TUR-BT) remains the initial management option. However, according to a large population-based survey by Wu et al. [9], the baseline characteristics of the two patient’s cohorts with recurrent BC after UTUC (UTUC-BC) and patients with primary BC were so different that the treatment guidelines for patients with primary BC were not fully applicable to the patients with UTUC-BC. For the UTUC-BC patients’ cohort, the majority of the patients were white (88.0%), male (58.7%), with a lower proportion of females (41.3%) and those with an earlier TNM stage. The median age of the patients with IVR was 72.07 years old, and the median BC tumor size was 24.36 mm. Compared to UTUC-BC patients, primary BC patients were more likely to be male (76.7%), with a larger median tumor size (34.84 mm) and earlier TNM stages (p < 0.001). The primary sites of tumor location were significantly different between the UTUC-BC and primary BC patients (p < 0.001), with the most common sites for UTUC-BC being the lateral wall and bladder neck, mostly presenting as NMIBC [10], while the primary BC patients were more likely to have tumors in the trigone of the bladder. For primary UTUC lesions in patients with UTUC-BC, the highest proportion of patients had renal pelvic carcinoma (74.7%), grade III/IV (67.6%), and stage N0 (91.0%).

The BC seems to be more difficult to treat than UTUC-BC does in terms of size and staging, but Miyake M et al. found that UTUC-BC had a worse prognosis with bacillus calmette-guérin (BCG) instillation in the bladder compared to that of primary BC, suggesting that these recurrent tumors inherently respond poorly to BCG [11]. Meanwhile, Shigeta K et al. also observed that the fibroblast growth factor receptor 3 (FGFR3) level was significantly lower in primary MIBC patients than it was in UTUC-BC patients (including NMIBC and MIBC, p < 0.01). In contrast, MIBC specimens (including IVR and primary BC) showed a higher expression of P53 levels than those of IVR of NMIBC specimens (p = 0.03 and 0.04, respectively) [12]. Increased expression of FGFR3 and P53 is frequently associated with tumor cell generation and progression, thus UTUC-BC might have characteristics such as being more aggressive in terms of growth and invasion. Interestingly, one study conducted by Wu et al., who investigated the prognosis of patients with BC, found that the cancer-specific survival (CSS) of UTUC-BC patients was not significantly different from the CSS of primary BC patients [9]. However, the CSS of the former group (11.4%) was significantly higher than that of the latter group (0.7%). Due to the impact of UTUC, the overall prognosis of UTUC-BC patients was worse than that of primary BC patients. The median survival times for UTUC-BC patients and primary BC patients were 54 and 97 months, respectively (p < 0.001). For the type of NMIBC, the median survival rates were 67 and 112 months for UTUC-BC and primary BC patients, respectively (p < 0.001) [9]. More importantly, the results demonstrated that neither radical cystectomy nor TUR-BT could provide a significant survival benefit for patients with UTUC-BC compared to that of the patients with primary BC who received the same surgical treatment. The study by Yates et al. indicated significant differences in the genetic and epigenetic background between the patients with UTUC-BC and primary BC [13], and these differences might be one of the factors that could result in the different treatment effects for the two patient cohorts with the same treatment strategy. Meanwhile, Makito et al. identified that patients with UTUC were more likely to develop IVR NMIBC after receiving intravesical BCG instillation compared with the likelihood of patients with primary NMIBC after matching UTUC-BC and primary NMIBC patients according to their propensity scores [11]. This was consistent with other existing studies and suggested that while BCG was currently one of the most effective intravesical agents for preventing recurrence of NMIBC, its role in disease progression still remained controversial.

Regardless of the tumor location, ORNU with bladder cuff excision has consistently been the standardized surgery in the management of patients with high-risk UTUC, and researchers recommend dissecting the ipsilateral medial cord ligament and lowering the ipsilateral bladder to facilitate the dissection of the whole distal segment of the ureter. The majority of the published works suggested that a minimally invasive approach might bring a more favorable perioperative outcome [84]. To lower the risk of tumor recurrence, oncological principles must be followed throughout the procedure, including the avoidance of access to the urinary tract, the avoidance of direct contact of instruments with the tumor, and using internal capsules to extract the specimens to prevent tumor seeding [85], the clamping of the ureter localized at the distal part of the UTUC tumor at an early stage to restrict the seeding of tumor cells into the bladder cavity in a downstream direction during renal and ureteral manipulation [72], and the resection of the upper urinary tract (kidney, ureter, and bladder cuff) intact [46]. Avoiding incomplete resection and ensuring negative surgical margins might contribute to lowering the recurrence rate. In addition, the surgery duration should be reasonably controlled to avoid an excessive operative time, which might cause the possibility of intracavitary metastasis and seeding tumor cells [70]. For tumors with pT > 2 stage, concomitant CIS, or extensive necrosis, surgeons should be more careful during the perioperative period [15,59]. It was mentioned previously that the involvement of lymph nodes is a risk factor for IVR [15]; therefore, researchers recommend that lymph node dissection should routinely performed for UTUC patients with pT > 2 stage, especially for high-risk patients. Given that the ureter is divided into upper, middle, and lower segments, the possibilities for lymph node dissection are very variable and would depend on the patient’s individual condition. Ureteroscopic biopsy and dialysis were mentioned earlier as independent risk factors for IVR [74,86], so minimizing the number of ureteroscopies and the number of dialysis preoperatively might also reduce IVR.

Intravesical therapy refers to the local adjuvant therapy in which chemotherapeutic drugs are instilled into the bladder cavity through a catheter to inhibit the growth of cancer cells in the bladder. The goals of local instillation therapy in UTUC are to reduce the risk of tumor recurrence and progression and to treat CIS [87]. The commonly used drugs are: mitomycin C (MMC), gemcitabine (GEM), pirarubicin (THP), etc. It has been shown that an immediate single bladder instillation of MMC prior to RNU or partial ureterectomy (within 3 h) could reduce the risk of bladder recurrence [88]. Alternatively, intraoperative bladder instillation of MMC is feasible and is not associated with the risk of complication [89]. Fang D et al. and Hwang EC et al. performed a meta-analysis including seven randomized controlled trials, and they found that early postoperative intravesical chemotherapy with MMC and THP could reduce the risk of bladder tumor recurrence within the first year after RNU [90,91]. Ito et al. treated UTUC patients with a single bladder instillation with 30 mg THP within 48 h after RNU and showed fewer bladder recurrences in patients who received THP instillation compared to those of the patients in the control group [92]. Due to existing studies, the timing of intravesical therapy also plays a differential role in the outcome. Noennig et al. compared intraoperative and postoperative bladder instillation by MMC, and they found that the one year bladder recurrence rate was significantly lower in the intraoperative group than it was in those patients who received postoperative MMC instillation [93]. In the timing of postoperative titration, a single dose of MMC given within 24 h after RNU to prevent recurrence was demonstrated to be more effective than delayed intravesical titration is within 48 h or 2 weeks postoperatively [94]. In addition to the timing of instillation, the frequency of instillation also affects the IVR of patients with UTUC. In a study by Huang Y et al., 270 patients were divided into three groups, which included multiple, single, and no instillation groups. These patients were instilled with epirubicin (30–50 mg per instillation, 125 patients), pirarubicin (30–50 mg per instillation, 89 patients), or mitomycin C (20–40 mg per instillation, 15 patients). The patients in both instillation groups were found to have a significantly lower recurrence rate compared to that of the no instillation group (13.1 vs. 25.4% vs. 41.5%, p = 0.001). Multiple instillation group had a higher bladder RFS rate than the single instillation group did [95]. These findings might suggest that the use of early and multiple intravesical treatment in the perioperative period could effectively reduce the probability of IVR for patients with UTUC.

The use of adjuvant intracavitary therapy has increased in recent years, with BCG being one of the first, and perhaps, the most studied adjuvant therapies. The use of BCG for the treatment of CIS is largely considered to be the standard of care in those who meet the criteria for intermediate or high-risk non-muscle invasive bladder cancer. Its use is supported by the American Urological Association (AUA) and European Association of Urology (EAU) guidelines. However, the efficacy of upper urinary tract remains uncertain and varies by dose variation, unique delivery mechanisms, and indication [96]. The study conducted by Rastinehad et al. reported 50 patients who received BCG instillation for the treatment of UTUC at Ta/T1 stages. However, there did not have any statistical significance between UTUC patients who received and who did not receive adjuvant BCG therapy [97]. The use of BCG might be more appropriate for CIS, as Carmignani et al. have shown that the induction process of BCG could convert a positive cytology to a negative one, with a mean recurrence rate of 32% at 19–57 months of follow-up. However, cytology negativity alone was not sufficient as a sign of remission [98].

In addition to intravesical instillation, neoadjuvant chemotherapy (NAC) has become a treatment option that has been received a lot of attention in recent years. Wu Z et al. analyzed 24 studies and found that NAC had a higher survival rate and better pathological response compared to those of surgery, but there were no more significant advantages compared to those of surgery plus adjuvant chemotherapy [99]. Therefore, the specific treatment modality and timing of NAC needs to be explored by more evidence-based research. Zennami K et al. studied a total of 184 UTUC patients grouped by whether or not they received NAC before RNU and found that high-risk UTUC patients who received NAC treatment had a significantly higher 5 year RFS than the controls did (80% vs. 61%, p = 0.001). A higher OS was also observed in patients with disease-staged ≤cT2 who underwent the NAC treatment (p = 0.019) [100]. Similarly, Shigeta K et al. studied 89 patients with UTUC who received NAC or conventional adjuvant chemotherapy and found that the NAC treatment before RNU could significantly improve RFS more than treatment with chemotherapy could (p = 0.039) [101]. Due to the nephrotoxicity of platinum-containing drugs, preoperative NAC, such as chemotherapy with gemcitabine + carboplatin and immunotherapy with PD-1/PD-L1 immunosuppressants was encouraged to optimize the surgical outcomes [102], especially for UTUC patients with a poor renal function. So, if the patient has normal renal function, the implementation of regimens with cisplatin instead of carboplatin could bring about better therapeutic results [103]. However, if the patient has poor renal function, then platinum-containing drugs should be avoided. Additionally, immunotherapy also plays a positive role in the prognosis of UTUC patients. Fradet Y et al. analyzed 542 UTUC patients treated with pembrolizumab or conventional chemotherapy, and they found that the one year OS rates and progression-free survival rates were higher in the UTUC patients group treated with pembrolizumab (44.2% and 12.4%, respectively) than they were in the chemotherapy group (29.8% and 3.0%, respectively), with a lower incidence of associated adverse events [104].

If a patient meets more of the above IVR risk factors, the frequency and length of follow-up should be increased to give appropriate consideration for the patient’s specific situation.

Bladder cancer and UTUC, although they are similar, are not identical in terms of biological nature and prognosis. As only a little is known about the natural course and disease characteristics of UTUC-BC, the frequency and specific time frame for the possible progression of superficial bladder cancer to invasive disease cannot be estimated either [108]. Therefore, even though some studies have investigated risk factors for the development of IVR in patients with UTUC, there have not been large-scale studies of the treatment strategies for patients with UTUC-BC [9,15,29]. Consequently, the current management for patients with UTUC-BC is similar to the current guideline-based treatment strategies for patients with primary bladder cancer [9,108]. For NMIBC patients with a history of UTUC (UTUC-NMIBC), transurethral resection of the bladder tumor (TUR-BT) remains the initial treatment option. For MIBC patients with a history of UTUC (UTUC-MIBC), radical cystectomy (RC) is commonly recommended [9].

A study by Wu J et al. showed poorer outcomes among UTUC-NMIBC patients after receiving RC, with a one year overall survival (1 yr OS) of 81.8% and a three year overall survival (3 yr OS) of 56.1%, while the patients undergoing TUR-BT had relatively good outcomes (1 yr OS: 86.6%; 1 yr OS: 65.6%) [9]. TUR-BT is both the first choice management option and an important diagnostic approach for patients with UTUC-NMIBC, contributing to a prolonged RFS for the patients. Mariappan et al. found that the lack of bladder detrusor in the specimen, as well as the presence of a residual tumor, was significantly associated with an increased risk of early recurrence in the bladder [109], which made the complete excision of tumors containing bladder detrusor particularly important. Two multifactorial analyses found that tumor concomitant CIS at the time of first IVR was an independent risk factor for UTUC-BC progression [110,111]. Therefore, if a patient was found to have concomitant CIS during surgery, more attention should be paid to the complete resection of the tumor specimen and to restrictively follow oncologic principles during surgery. There was also a reduced recurrence rate when narrow band imaging (NBI) was used during TUR-BT [112].

Tanaka N et al. investigated 241 patients with UTUC-BC after receiving RNU. Among them, the cumulative incidence rates of recurrent IVR at 1 and 5 years after treatment were 31.0% and 48.4%, respectively [111]. For the treatment of patients with such a high recurrence rate, ERBT is gradually becoming an alternative treatment to conventional TUR-BT. ERBT can obtain a complete bladder tumor specimen, allowing the pathologist to make a more accurate diagnosis of the incision margin and depth of infiltration, with it being conducive to acquiring accurate pathological staging and achieving clinical significance for postoperative bladder perfusion protocols, prognosis, and individualized follow-up program [113]. For patients with UTUC-NMIBC, ERBT was more feasible, safer, with fewer intraoperative complications than those of conventional TUR-BT, and it resulted in less remaining tumors and was unlikely to be replaced by TUR-BT [114]. It is more likely that the secondary resection could be avoided by good en block resection and might gradually become the main therapeutic modality for patients with UTUC-NMIBC in the future. Additionally, with the development of medical laser technology, there are more wide-spread lasers being used in TUR-BT, and some studies argued that TUR-BT using lasers could achieve more satisfactory treatment effects with a better prognosis than traditional electric TUR-BT can.

A considerable number of patients with UTUC-NMIBC will experience tumor recurrence after electrotomy due to factors such as tumor stage, size, numbers, and the surgical skill of the surgeon. Therefore, for those recurrent patients, researchers need to repeat TUR-BT (reTUR), which requires the resection of the basal part of the original tumor area (including the surrounding mucosal inflammatory edema area) and the suspected tumor site. It is necessary to resect into the deep muscular layer of the bladder. Meanwhile, it is advised to make multiple randomized biopsies from the bladder wall. A reTUR can increase the RFS, improve the outcomes after BCG treatment, and provide prognostic information [115]. Because there are only a few surgical data about patients with UTUC-NMIBC, surgeons should decide when to perform reTUR based on the patient’s individual characteristics (e.g., concomitant CIS, etc.).

There are surgical options for both types of UTUC-BC, yet there are only a few data showing improved survival in UTUC-BC patients treated with these therapies [9]. Two multifactorial analyses have shown that the failure to perform intravesical therapy is an independent risk factor for disease progression for patients with UTUC-BC [12,111]. Therefore, intravesical chemotherapy is essential in the treatment program. Intravesical instillation has been shown to be effective by destroying circulating tumor cells after TUR-BT by ablating tiny residual or neglected tumor cells at the resection site [116].

It has been shown that tumors in patients with UTUC-BC respond more poorly to BCG than those in the patients with primary BC do [11]. Therefore, instillation drugs with higher sensitivity should be selected for patients with UTUC-B, and normal saline with MMC, epirubicin, or pirarubicin showed beneficial effects [117]. In a randomized controlled trial, the experimental group of normal saline combined with gemcitabine was superior to the placebo control (saline) group, with significantly lower toxicity [118]. Gemcitabine has been shown to have a response rate no less than that of the existing standard MMC and has several other advantages, including lower toxicity and costs [118].

To further improve surgical outcomes, some studies had shown that the introduction of photosensitizers for photodynamic diagnosis (PDD) during TUR-BT could improve the complete detection of tumors and reduce residual tumors more compared to that of white light cystoscopy (WLC), but it had no significant advantage over conventional WLC in terms of diagnostic accuracy [119,120]. In addition to this, Wu J et al. found that patients with UTUC-MIBC who previously received radical cystectomy (RC) did not have significantly better survival compared to those who had tumor resection by TUR-BT [9]. The above treatment modalities are roughly the same as those for primary BC. So, physicians can make an appropriate treatment strategy when they are treating patients with UTUC-BC according to the treatment guidelines for primary BC.