Laparoscopic versus open nephroureterectomy to treat localized and/or locally advanced upper tract urothelial carcinoma: oncological outcomes from a multicenter study

Upper urinary tract urothelial carcinoma (UTUC) is a relatively rare malignancy. It is estimated to comprise 10% of all renal tumors and 5% of urothelial carcinomas overall [1]. Open radical nephroureterectomy (ONU), with excision of the ipsilateral bladder cuff, is the standard treatment for UTUC [2, 3]. However, laparoscopic radical nephroureterectomy (LNU), first performed by Clayman et al. in 1991, has emerged as an accepted minimally invasive treatment alternative to ONU [4]. Subsequently, there have been numerous retrospective reports comparing the oncological outcomes between ONU and LNU [5‐18] and one prospective series [19]. To date, none of the studies have shown a significant difference between the techniques in terms of overall survival (OS), recurrence-free survival (RFS), and cancer-specific survival (CSS). Only one study showed that there was a trend toward an independent association between surgical approach and RFS [13], and three studies showed a higher risk of intravesical RFS with LNU [7, 20, 21]. However, these studies focused on the oncological outcomes among the entire cohort of UTUC patients. Especially, they included a great many pTa stage and organ-confined UTUC. As experience with LNU grows, case selection has expanded to include more complex cases, resulting in carefully selected localized and/or locally advanced UTUC and larger tumors being operated on laparoscopically. However, until recently, only one study has focused on the oncological outcomes of LNU in the subgroup of localized and/or locally advanced UTUC [22]. Hence, the present study aimed to compare intravesical RFS, overall RFS, CSS, and OS between ONU and LNU for localized and/or locally advanced UTUC (T_1–4/N_0-X), performed in two Chinese tertiary teaching hospitals.

Clayman et al. performed the first successful LNU in 1991 [4]. Multiple reports have since described the efficacy of LNU for favorable-risk UTUC patients regarding cancer control [5‐19]. In recent years, experienced surgeons have expanded their criteria for LNU for large or locally advanced UTUC, which indicated the effectiveness of laparoscopic surgery. To compare the efficacy of LNU and ONU in localized and/or locally advanced UTUC, we performed the present study, including 265 patients with T_1–4/N_0-X UTUC (213 ONU vs. 52 LNU) treated with RNU. The Kaplan-Meier plot illustrated no significant difference in survival between the two groups of different procedures. Multivariate analysis suggested the equivalence of LNU and ONU in terms of intravesical RFS, overall RFS, CSS, and OS. During the later courses of our study, Kim et al. [22] reported that the 5-year OS and CSS rates were lower in the LNU group than in the ONU group in patients with locally advanced UTUC. Furthermore, on multivariable analysis, LNU was found to be an independent predictor of poorer OS and CSS than ONU. However, the study has some limitations: On the one hand, the cohort patients included N+ disease. On the other hand, the study did not analyze the cigarette smoking status, despite the fact that exposure to smoking is a significant risk factor for bladder urothelial carcinoma as well as UTUC. Thus, the comparison between Kim’s study and our study is difficult to make.

It is essential to follow the oncological principles and the established surgery procedure for laparoscopic surgery in urothelial carcinomas [8, 11, 14]. According to previously published papers, tumors cells may undergo retroperitoneal metastatic dissemination and dissemination along the trocar pathway under pneumoperitoneal circumstances during operation. Initial researchers despised laparoscopic operation in urothelial carcinomas because the high-pressure environment of pneumoperitoneum was thought to promote tumor dissemination and recurrence. To our best knowledge, only 12 cases of laparoscopic port-site seeding are available in English literature [23]. In our study, only one case was seen in our early experiences, which may be associated with the limited use of laparoscopic bags in the early days. Nowadays, precautionary measures have been taken into consideration to prevent potential tumor spillage. It has been stressed that direct contact between the instrument and the tumor should be forbidden during dissection. Besides, LNU must be accomplished in a closed system.

In patients with organ-confined UTUC, LNU has the advantage of minimal invasiveness and has oncological outcomes comparable to those of ONU. However, its effectiveness in patients with localized and/or locally advanced diseases remains to be proven, and the results were contradictory. Our findings were consistent with results from one single center study [10] and two recent multi-institutional studies [4, 9], which showed no independent association between surgical approach and survival, in both organ-confined and advanced UTUC patients. Unfortunately, some authors reported that relative to ONU, LNU was associated with an adverse prognosis in advanced stage patients. Fairey and colleagues [13] published a multi-institutional retrospective study comparing ONU and LNU in 849 patients. These authors report equivalent OS and CSS for the surgical approaches. However, there was a trend toward an independent association between surgical approach and RFS (OR 1.24, 95% CI 0.98–1.57, P = 0.08). Furthermore, when stratifying by stage on multivariate Cox regression models, LNU was independently associated with poorer RFS in patients with ≤ pT2N0 and pTanyN1-3 disease: however, there was no independent association between surgical approach and RFS in patients with pT3-4 N0 disease. In the only prospective randomized study published in the literature, Simone and colleagues [19] reported 80 UTUC patients treated with ONU (n = 40) and LNU (n=40). After a median follow-up of 44 months, for organ-confined disease, the two groups did not differ significantly in the rates of intravesical RFS and CSS. However, when matched for pT3 and high-grade tumors, CSS and metastasis-free survival were significantly different between the two groups, in favor of ONU.

However, the conclusions based on previous results are underpowered because of the different statistical models used. The factors of UTUC tumor location [24, 25], previous bladder tumor history [26, 27], and previous hydronephrosis [28, 29] should be included in the model because the predictive significance of these factors remains controversial. Additionally, cigarette smoking status should be included in the analysis because exposure to smoking is a significant risk factor for bladder urothelial carcinoma as well as UTUC [30]. Furthermore, imbalances are apparent in some of these important series [9, 11, 13]. The LNU group contained tumors at lower stages and they had a lower rate of LVI. These differences, were statistically significant. This may be compensated for by the multivariate analysis and further corrected using various statistical techniques; nevertheless, it reflects significant patient selection in which, generally speaking, LNU was avoided in the higher stage cases. Thus, because of the smaller proportion of higher stage cases performed laparoscopically, the overall outcome was skewed by the good prognosis of the lower stage cases. In comparison with previous results, our groups were better matched for prognostic factors, such as tumor stage, grade, and LVI, and we include some controversial elements, such as tumor location, previous bladder tumor history, and previous hydronephrosis. Therefore, we could draw more relevant conclusions. In addition, several limitations of this study should be mentioned. First, the data were collected retrospectively and reflect the experiences of two institutions. Furthermore, different bladder cuff managements were used between the LNU and ONU groups. Second, the majority of patients were underwent open procedures; moreover, the laparoscopic cohort included those operated on using retroperitoneal and transperitoneal approaches. Third, pathological specimens were not subjected to a centralized review. In additon, the follow-up period was relatively short.

In summary, after a median follow-up of 60.0 months, oncological results were comparable between LNU and ONU for the treatment of localized and/or locally advanced UTUC (T_1–4/N_0-X). Our data could be used as evidence for equivalent cancer control outcomes between LNU and ONU in patients with T_1–4/N_0-X UTUC. Further analyses, including randomized trials, are needed to generalize these conclusions to patients with more unfavorable disease characteristics.