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Introduction

Urothelial carcinomas (UCs) are the fourth most prevalent malignancies in men. Although 90-95% of urothelial carcinomas are located in the lower tract (bladder and urethra), 5-10% of them are located in the pyelocaliceal cavities and ureter and known as upper tract urothelial carcinoma (UTUC) [1].

UTUCs can be classified into low- or high-grade tumors. Low-grade tumors are generally not invasive whereas high grade tumors tend to be aggressive and invasive in the kidney or ureter [34]. At diagnosis, two-thirds of UTUC tend to be invasive while only 15–25% of bladder tumors are invasive [2].

Despite treatment with curative intent, UTUC has a high recurrence risk [3] with five-year cancer specific survival less than 50% for pT2/T3 and less than 10% for pT4 [4].

A retrospective review of the MD Anderson Cancer Center’s experience found no improvement in the disease specific survival of UTUC over an 18-years period and suggested a change in the treatment protocol [5]. Thus, improved management of early-stage disease has the potential to save lives [6].

To time, radical nephroureterectomy (RNU) with lymph node dissection remains the current standard of care [3]. However, several studies have showed that kidney-sparing surgery (KSS) was equivalent to radical nephroureterectomy (RNU) in term of CSS (cancer specific survival) in patients with low-risk UTUC [32, 33]. However, radical nephroureterectomy (RNU) remains the standard for high-risk UTUC [34].

In practice, due to the rarity of this entity, there is a lack of high-level evidence-based guidelines and the optimal management of UTUC is based on retrospective limited studies and consisted more probably on extrapolation from bladder cancer approaches which could be not suitable for UTUC [7].

This critical review will summarize the current data on adjuvant therapy in UTUC focusing on the differences between UTUC and bladder cancer and the expected role of immunotherapy.

Adjuvant chemotherapy in bladder cancer

The role of adjuvant chemotherapy in bladder cancer remains a debatable approach and has not been established by a randomized trial. One of the largest randomized trials, the European Organisation for Research and Treatment of Cancer (EORTC) 30994 trial, showed among 284 patients treated with radical cystectomy an improvement in term of five-year PFS (48% versus 32%; HR 0.54, 95% CI 0.40-0.73) but failed to show a significant improvement in overall survival compared to those assigned to observation [five-year OS (54% versus 48%; HR 0.78, 95% CI 0.56-1.08)] [11,12]. However, several studies have shown a benefit of adjuvant chemotherapy in a specific group of patients having a high-risk disease [12,13]. For instance, a prospective study was published by Haquet et al., showed a longer OS in patients with N2-3 disease (17.5 vs. 14.4 months; p = 0.005) or with positive surgical margins (16.7 vs. 12.2 months; p = 0.025) [12]. Taking all the available data into account, the role of adjuvant chemotherapy in bladder cancer remains unclear. Nevertheless, given its benefits in selected patients, adjuvant chemotherapy can be offered to high-risk bladder cancer patients who did not receive neoadjuvant treatment.

Adjuvant chemotherapy in UTUC

The effectiveness of adjuvant chemotherapy in UTUC seems less controversial compared to the bladder. Several retrospective studies, meta-analyses and one randomized trial had evaluated the benefit of adjuvant chemotherapy in UTUC.

In 2014, in a retrospective study, Yafi et al. showed that adjuvant chemotherapy did not improve survival in UTUC patients. He showed also that 57% of the high-risk patients became ineligible for adjuvant chemotherapy because of poor postoperative renal function. This has led to the use of suboptimal regimen or doses which may explain the negative results [14].

Moreover, in 2017, Necchi et al. conducted a joint study to evaluate the efficacy of adjuvant chemotherapy in UTUC patients. The study results, though not statistically significant, showed shorter OS (HR 1.25, 95% CI 1.02–1.54) in the adjuvant chemotherapy arm. This phenomenon can be explained by the fact that the patients who received adjuvant chemotherapy had a more advanced disease [15].

The effectiveness of adjuvant chemotherapy was compared for the upper tract and lower tract urothelial carcinoma in a meta-analysis published by Jazayeri et al in 2018. The report showed that adjuvant chemotherapy was more effective in LTUC: DFS (HR 0.41, 95%CI 0.31-0.54), CSS (HR 0.29, 95%CI 0.17-0.50) and OS (HR 0.51, 95%CI 0.38-0.70) versus UTUC: DFS (HR 0.61, 95%CI 0.1–0.93) and CSS (HR 0.70, 95%CI 0.56–0.90) rates, with no effect on OS (HR 0.87, 95%CI 0.69–1.10). Moreover, differences in CSS and OS were significant (p < 0.0001) in favor of adjuvant chemotherapy for LTUC versus UTUC [21].

In 2020, a meta-analysis was published by Quhal et al. and showed that adjuvant chemotherapy improved metastasis-free survival and cancer-specific survival in both, localized and locally advanced UTUC. However, in terms of OS, the benefit of adjuvant treatment was only seen among patients with locally advanced UTUC (HR 0.80, 95% CI 0.71–0.90, p < 0.001) [16].

However, in contrast to these upper mentioned equivocal results, in 2014, a meta-analysis was published, including one prospective study and nine retrospective studies, with a total of 482 patients receiving adjuvant chemotherapy after nephroureterectomy and 1300 patients treated with nephroureterectomy alone. The pooled evidence showed a benefit of cisplatin-based adjuvant chemotherapy in term of OS and DFS with a respective HR of 0.43 (95% CI, 0.21–0.89; p = 0.023) and 0.49 (95% CI, 0.24–0.99; p = 0.048). No benefit was seen for non-cisplatin-based regimen [17].

Another positive report, a prospective comparative trial on 176 patients (94 patients in the adjuvant chemotherapy group and 82 patients in the observation group), found an improvement of the survival outcome of high‑risk UTUC patients. In fact, adjuvant chemotherapy had significantly improved PFS [P = 0.0033, HR = 3.78 (3.13–4.55)], OS [P = 0.0397, HR = 1.39 (1.01–1.75)] and cancer specific survival [P = 0.0255, HR = 1.26 (1.07–1.45)] in this population. In the subgroup analysis, a significant improvement with adjuvant chemotherapy was obtained in the lymph node positive subgroup in term of PFS (11.4 months vs. 31.9 months, P = 0.0018), OS (26.8 months vs. 36.3 months, P = 0.0255) and CSS (28.2 months vs. 39.3 months, P = 0.0197). Similarly, in the T3/4 cohort, adjuvant chemotherapy has improved median PFS (13.9 months vs. 36.3 months, P = 0.0217), OS (20.6 months vs. 32.2 months, P = 0.0183) and CSS (21.9 months vs. 38.4 months, P = 0.0226). [18]

An observational study on 3253 patients, published by Seisen et al in 2017, aimed to evaluate the effectiveness of adjuvant chemotherapy in patients with pT3/T4 and/or pN+ UTUC. Results showed that median OS was significantly longer for adjuvant chemotherapy versus observation (47.41 [interquartile range,19.88 to 112.39] vs 35.78 [interquartile range, 14.09 to 99.22] months; P < .001) [19].

Also, in 2017, a retrospective Japanese study on 449 patients was published to evaluate adjuvant chemotherapy in selected high-risk patients with UTUC. Results showed significant improvement in term of 5-years CSS (p=0.02) in favor of the chemotherapy group compared with the non-chemotherapy group [20].

All these previous studies were limited either by the small numbers or by selection biases from their retrospective nature with low statistical power and conflicting conclusions [15,17,22]. However, in 2020, the results from the prospective randomized POUT trial were published. POUT was a phase 3, open label, randomized controlled trial aiming to evaluate DFS benefit of 4 adjuvant cycles of platinum and gemcitabine versus surveillance in 261 UTUC patients. Adjuvant chemotherapy significantly improved DFS (hazard ratio 0·45, 95% CI 0·30–0·68; p=0·0001). This result was maintained even with additional follow-up, but when it comes to OS, no statistically significant reduction was achieved (HR = 0.72, 95% CI: 0.47-1.08; p = 0.11; adjusted HR = 0.79, 95% CI: 0.52-1.19; p = 0.26). The 3-year event-free estimates were 71% (95% CI 61–78) and 46% (36-56) for adjuvant chemotherapy and surveillance, respectively [23].

Given all this available data and based especially on POUT results, current recommendations consider the option of adjuvant chemotherapy in UTUC as a suitable therapeutic approach.

Adjuvant Immunotherapy

Since 2017, immunotherapy has changed the treatment paradigm of urothelial carcinoma. Three studies have evaluated the adjuvant role of immunotherapy in muscle-invasive bladder cancer including patients with UTUCs.

The first study, the IMvigor 010 trial, was disappointing. 809 patients, with confirmed high-risk muscle invasive urothelial carcinoma treated with radical surgery, were randomly assigned to receive either adjuvant atezolizumab or observation. The trial did not meet its primary endpoint of improved disease-free survival in the atezolizumab group over observation. In the sub-group analysis, median disease free-survival in UTUC patients was 14.2 months (95% CI 5.6-NE) for the atezolizumab group versus 28.1 months (95% CI 6.8-NE) for the observation group [HR1.25 (95% CI 0.57-2.74)] [3].

Few months later, data from CheckMate 274 presented at the 2021 ASCO meeting gave new hopes. In this trial, 709 patients with confirmed high-risk muscle invasive urothelial carcinoma treated with radical surgery, were randomly assigned to receive nivolumab or placebo. Disease-free survival was longer with adjuvant nivolumab than with placebo in the intention-to-treat population [20.8 months ;95% confidence interval [CI], 16.5 to 27.6 versus 10.8 months; 95% CI, 8.3 to 13.9] [24]. On August 19,2021, nivolumab received the FDA approval for adjuvant treatment of patients with high-risk urothelial carcinoma [25]. However, when it came to the subgroup analysis of the 149 patients with UTUC, despite the significant benefit noted in bladder cancer patients [HR 0.63 (95% CI 0.49-0.78)], no benefit was noted in this subgroup, either in renal pelvis located cancer patients [HR 1.23 (CI 95% 0.67-2.23)] nor in ureter located cancer patients [1.56 (CI 95% 0.7-3.48)] [24].

These two studies had provided conflicting results concerning the efficacy of adjuvant immune checkpoint inhibitors (ICIs) in the whole high-risk muscle invasive urothelial cancer population, despite being conducted in similar settings. This divergence could be partially explained by the difference in the control arm where it was observation in IMvigor 010 and placebo in Checkmate 274 leading to a higher dropout with atezolizumab and the sparing of cumulative censoring with nivolumab [26]. However, in both trials, the UTUC subgroups failed to benefit from adjuvant ICIs. Available studies on adjuvant therapies in UTUC are summarized in table 1.

Presently, results from AMBASSADOR trial with Pembrolizumab are awaited. In this trial 739 patients with confirmed high-risk muscle invasive urothelial carcinoma treated with radical surgery, were randomly assigned (1:1) to receive pembrolizumab or observation [27].

Other Approaches

To time, no study has evaluated the effect of combining immunotherapy and chemotherapy in the adjuvant setting. A new study, POUT-2, in which the original 75 centers in the POUT trial and international centers will be invited to participate [28], is being developed to compare adjuvant therapy with chemotherapy alone versus chemotherapy/immunotherapy [29].

On the other hand, targeted therapy has emerged as an option in the management of urothelial carcinoma. More specifically, infigratinib (BGJ398), a selective FGFR1–3 inhibitor, has shown promising clinical activity and tolerability in patients with advanced urothelial carcinoma having FGFR3 alterations [30]. Of note, fibroblast growth factor receptor 3 (FGFR3) genetic alterations occur in up to 70% of UTUC and up to 20% of TTUC (total tract urothelial carcinoma). PROOF 302 was conducted to evaluate the efficacy of infigratinib as adjuvant therapy in patients with high-risk invasive urothelial carcinoma (including UTUC) and FGFR3 alterations. In this trial 208 patients with confirmed high-risk muscle invasive urothelial carcinoma treated with radical surgery, were randomly assigned (1:1) to receive oral infigratinib or placebo. The results are awaited [31].

Conclusion

Adjuvant therapy remains controversial in urothelial carcinoma especially in UTUC. However, adjuvant chemotherapy has succeeded to make its way as a good option in high risk UTUC patients based on the positive results of the POUT phase III trial. But, when it comes to immunotherapy in the adjuvant setting, despite being almost beneficial in bladder cancer patients, at least with nivolumab, it has failed to do so in UTUC patients. Other approaches in the adjuvant setting, as targeted therapy or combining chemo-immunotherapy, are still under evaluation.