The endpoint of effectiveness (both renal function preservation and curative resection) was compared with the “historical control,” which was LPN performed at multiple institutions in Japan (541 institutions, 1,375 cases). The achievement rate of both renal function preservation and radical resection, which were the primary endpoints of the present trial, was 91.3% (95% confidence interval, 84.1–95.9). This value significantly exceeded the threshold level (23.3%) determined beforehand (p<0.001).

Renal ischemic time under 25 minutes is an important indicator of renal function preservation. According to the existing research, patients with less than 25 minutes of renal ischemic time have significantly less impaired renal function 6 months postoperatively and significantly lower incidence of CKD (CKD stage IV; <30% eGFR), compared with those having ischemic time over 25 minutes. A multi-institutional observational study used as a historical control suggested that with LPN the renal ischemia time was 25 minutes or less in 25% of patients at most. When planning this project, we hypothesized that increasing the percentage of patients with renal ischemic time of 25 minutes or less by 5% to 10% (corresponding to the number needed to treat=10–20) with the RAPN protocol would be clinically significant. To achieve a significant change in medical economics it was determined that an increase of 15% would be required, taking into account the incremental costs related to the introduction of this novel treatment. Accordingly, the expected percentage of RAPN patients with renal ischemic time within 25 minutes was set at 40%. Additionally we anticipated that approximately 37.2% of patients would achieve the primary endpoint of both renal function preservation and curative resection, taking into account that in some cases RAPN would need to be converted into conventional laparoscopic or open surgery, or would have positive surgical margins. In the present prospective trial, 91.3% of patients achieved both renal function preservation and curative resection, far exceeding our expectations.

Thus, the results of this trial revealed good efficacy with RAPN, compared with the historical control. The historical control used to set the basis of threshold was reported in 2012 based on data from a multi-institutional observational study on LPN (54 institutions, 1,375 cases) conducted in Japan from 1998 to 2008 [17]. That study reported that ischemic time in laparoscopic surgery had decreased in recent years. Therefore, when comparing the results of the two studies, it may be necessary to consider differences in the technical maturity between the present and the time when the multi-institutional joint observational study on LPN was performed. However, even if this difference in technical maturity is taken into consideration, the results of the present study show an obvious advantage of RAPN.

When ischemic time alone was examined, we found a clear shortening compared with historical controls (mean±standard deviation: 19.0±6.4 minutes for RAPN, 41±19 minutes for LPN). There were no positive surgical margins. The reported rates of positive surgical margins with LPN were 0% to 4% [18192021222324]; the rate of the historical control was 1.7%. These values indicate the effectiveness of RAPN for cancer control. These excellent results were due to the features of a robot-assisted approach, such as precise 3-dimensional visualization, highly flexible forceps with 7 degrees of freedom, and the correction of tremor. Although it is difficult to perform LPN in some cases, depending on conditions such as tumor diameter or location even in the case of T1 tumors, RAPN had good results, with no big difference in achievement rate regardless of the diameter or location of the tumor.

When an analysis object group (full analysis set) was evaluated with the R.E.N.A.L. nephrometry score, which is an index of the difficulty of partial nephrectomy mainly based on tumor location and diameter [25], we found 38 low-complexity cases (36.9%), 62 intermediate-complexity cases (60.2%) and 3 high-complexity cases (2.9%). These percentages are comparable to the patient composition in past reports (48 low-score cases [44%], 57 intermediate-score cases [53%], and 3 high-score cases [3%]), which reveals that arbitrary patient selection was not performed. In addition, although we have only short-term results at present, there was no report of death, and the probability of survival for 90 days after surgery was 100.0%. A comparison of outcomes in past studies and in the present trial is shown in Table 1. Longer average length of hospital stay observed in the present study was due to Japanese public health insurance system; burden of hospitalization cost is light in Japan. Observation is ongoing in this trial.

The positive surgical margins rate in this study was 0%. Compared with the results of the historical control (1.7%), this result suggests the effectiveness of RAPN. With respect to the tumor location, the protocol treatment was performed evenly in all locations and the achievement rate of the primary endpoint was as high as 87.5%–93.7%, irrespective of tumor location. As mentioned above, in cancer control (negative margin rate) and renal function preservation (ischemic time within 25 minutes), RAPN achieved better results than conventional laparoscopic surgery. Comparison of surgical efficacy in reported and present studies were shown in Table 1. Achievement of primary outcome according to background characteristic factors was shown in Table 2.

The operative time (mean±standard deviation) in this trial was 3.89±1.10 hours; blood loss was 60.78±94.50 mL. Compared with clinical studies on RAPN performed in other countries and those on LPN in Japan, surgery time was almost the same (historical control, 4.32±1.52 hours). Blood loss, however, was less with RAPN than with the conventional surgical procedure (210±426 mL for historical control). Among safety analysis object groups, the rate of adverse events during the operation was 53.3% (56 of 105), which was high compared with the rate of postoperative complications (10.6% [11 of 104]).

The serious adverse event in this study was postoperative renal arterial aneurysm (9 cases). Renal artery aneurysm is a known complication after OPN or LPN. When the renal artery is damaged during suturing after tumor resection, or if insufficient hemostasis in the thin vulnerable renal artery results in rebleeding when blood flow increases after surgery, hematoma around an artery in resected defects can form a pseudoaneurysm. The main sign of pseudoaneurysm is macrohematuria. In this study we examined the relationships between pseudoaneurysm and sex, age, body mass index, anamnesis, tumor location, and Renal Nephrometry Score. No correlation was found with any of these factors. Three cases of aneurysm, however, were reported from a single institution. Those cases might have resulted from inexperience of the surgeon.

The reported probability of symptomatic aneurysm with signs such as macrohematuria is 0.4%–4.2% in OPN, 1.0%–12.0% in LPN, and 0.2%–10.2% in RAPN. These numbers, however, vary depending on the report [26272829303132]. In one study in Japan, asymptomatic renal pseudoaneurysm was detected with enhanced computed tomography in 17 out of 117 early postoperative patients (15%) after RAPN [33]. According to that report, arterial embolization was performed in 1 case that had bleeding and in 11 cases to prevent future bleeding (size≥4 mm), though they were asymptomatic. The other 5 cases were followed up and regressed naturally. Therefore, even though pseudoaneurysm can occur, small pseudoaneurysms generally follow a course of natural regression. The number that could have become symptomatic and caused clinical problems was 12. Therefore the estimated incidence of symptomatic aneurysm is 10.2% (12 of 117). In the present study pseudoaneurysm occurred in 8 cases (7.6%), indicating that renal pseudoaneurysm did not occur frequently.

The preferred treatment of pseudoaneurysm is coil embolization via arterial catheter because of its low invasiveness and high success rate. However, invasive laparotomy is sometimes required [2644]. All cases of pseudoaneurysm in the present study were mild and recovered with minimally invasive catheter coil embolization. This is because the artery that caused rebleeding was quite small and hemostasis of the main arteries was ensured with the precise manipulation of the robot-assisted approach. Pseudoaneurysm is an adverse event that can occur after RAPN; this possible complication must be kept in mind during postoperative patient care, and must be treated quickly and appropriately when it does occur.

Another complication of partial nephrectomy is urine leakage. When open tumor resection of the renal pelvis or calyx is performed, urine can leak into the abdominal cavity from the suture line, and can cause clinically significant effects. In the historical control, urine leakage was found in 2.5% of all patients and in 1.7% of those who were grade 3 or higher. There were no reports of urine leakage in our trial. This is a point that should be noted, because it shows the advantages of robotic assistance. Robotic assistance allows easy and accurate suturing compared with a conventional laparoscopic approach, enables surgery to be performed with an enlarged field of view, and provides secure suturing in the case of open resection of the renal pelvis or calyx.

Other defined adverse events in this trial were bleeding, venous thrombosis, pulmonary embolism, wound infection, multiorgan damage, renal hypertension, wound infection, and acute renal dysfunction. The events reported during the observation period were 29 cases of bleeding (27.6%) and 3 of acute renal dysfunction (2.9%). In the patients with acute renal dysfunction, the serum creatinine level rose transiently, with a decrease in eGFR. Each of these cases recovered without becoming critical. The frequency and outcome of bleeding and acute renal dysfunction were not different from those of other treatments in this domain. The rate of adverse events was evaluated according to background factors. No factors correlating with adverse events were identified, although the number of examples of each background factor varied. The adverse events that occurred most frequently in the perioperative period were wound complications (31 cases), macrohematuria (22 cases), and fever (13 cases), all of which occur frequently with any surgical procedure.

eGFR, which is an indicator of renal function, never fell below 60 mL/min/1.73m² in any patient after protocol treatment and showed recovery with passage of time, indicating preservation of renal function. Thus RAPN appears to effectively preserve renal function. Moreover, in 91.3% of cases resection and suturing were performed within 25 minutes, which is considered the cutoff for ideal ischemic time. Minimizing renal ischemia time leads to long-term preservation of renal function and to the control of progression to CKD, contributing significantly to the improvement in patients' quality of life.

Among safety analysis object groups, 146 postoperative adverse events were reported in 56 patients, yielding a complication rate of 53.3% (56 out of 105 cases). The adverse event that occurred most frequently in the perioperative period was wound complications (31 cases, 29.5%), followed by macroscopic hematuria (22 cases, 21.0%) and fever (13 cases, 12.4%). The perioperative critical adverse event that occurred most frequently in this trial was symptomatic pseudoaneurysm in 8 cases (7.6%). It is known, however, that renal pseudoaneurysm sometimes occurs after partial nephrectomy. The incidence of pseudoaneurysm in this trial was not particularly high. Comparison of safety outcomes of previous and current studies were shown in Table 3.

Fourteen Japanese institutions participated in this trial. The console surgeons were required to have experienced more than 10 cases of RAPN. Furthermore, they were required to meet the following conditions: experience of more than 10 cases of laparoscopic or open partial nephrectomy, more than 30 cases of laparoscopic or open radical nephrectomy, more than 20 cases of robot-assisted radical prostatectomy, and approved as laparoscopic surgeon by the Japanese Society of Endourology. Although the experience of 10 cases of RAPN cannot be considered vast experience, 91.3% of patients attained the primary endpoint.

Although mastering this technology takes some training and technical experience, as with open surgery or conventional laparoscopy, it is possible to gain the skills in a short period of time. Accordingly RAPN is considered to be a useful surgical technique to minimize invasiveness, provide radical cancer curability and preserve renal function. Surgery for renal hilar tumors and full endophytic-type tumors has been considered difficult with a conventional laparoscopic approach. In the future, however, a robotic approach will make it possible to remove such tumors with minimal invasiveness, which has previously been attained only through open surgery.

This study found that RAPN achieves minimal invasiveness, good cancer control, and renal function preservation, indicating that this technology will improve the surgical treatment of patients with nonmetastatic RCC, will decrease the occurrence of postoperative CKD, and will improve long-term prognosis. RAPN will contribute considerably to the public health, which will lead to reduced medical expenses.