Author s response to reviews

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1 Author s response to reviews Title: Robot-assisted radical prostatectomy significantly reduced biochemical recurrence compared to retro pubic radical prostatectomy Authors: Tetsuya Fujimura (tfujimura-jua@umin.ac.jp) Hiroshi Fukuhara (hifukuha@bk9.so-net.ne.jp) Satoru Taguchi (satorutaguchi33@gmail.com) Yuta Yamada (yyamada2029@gmail.com) Tohru Nakagawa (tohru-tky@umin.ac.jp) Aya Niimi (fum6134@yahoo.co.jp) Haruki Kume (kume@kuc.biglobe.ne.jp) Yasuhiko Igawa (yigawa-jua@umin.ac.jp) Toru Sugihara (ezy04707@nifty.com) Yukio Homma (homma-uro@umin.ac.jp) Version: 1 Date: 10 Mar 2017 Author s response to reviews: Reviewer 1 Comments 1. Fujimura and colleagues report a retrospective comparison of robot versus open prostatectomy at U. Tokyo hospital, assessing records over 12 years of 914 pts. This is apparently the first series examining Asian pts in a first-world setting. This is a nice case series with an interesting result with regards to better outcome for robot assisted surgery, but lacks context. It is unclear why this study is more appropriate for BMC Cancer than BMC Urology, where similar studies have been reported and the audience is more attentive.

2 Thank you for your positive comments. We believe that the present study is suitable for publication in BMC cancer because prostate cancer is prevalent, and the present study may be of major significance for oncologists around the world. 2. Conclusions section-first sentence belongs in methods, no other conclusions. We concluded as follows: RARP versus RRP is associated with improved PSM and BCR. To examine the cancer-specific survival, further investigations are needed (On page 2, Abstract, last). 3. Background/Introduction significantly lacking discussion of many studies over the past five years that address this question Yaxley'16 (included in discussion but not the table), Hu'14, Alemozaffar'16 are the ones that come to mind, but surely others are on topic, and the results from these inform the current study and put it in context. Might also include some of the other comparisons of surgical and quality of life/functional outcomes. These and other more recent studies should be included in the discussion. We have added two references according to reviewer s suggestions including the following: Hu JC (ref. 5) and Alemozaffar M (ref.6). We have revised Introduction, Table 4, and Discussion as follows: On page 4, line 1; Robot-assisted radical prostatectomy (RARP) is widely used to treat localized prostate cancer (PC) [1]; nevertheless, there have been no large randomized controlled trials demonstrating its superiority over retro-pubic radical prostatectomy (RRP) [2, 3]. A randomized controlled study very recently conducted on 326 patients with localized PC equally allocated to RARP or RRP did not show its advantage over RRP [4]. On the contrary, RARP was associated

3 with improved positive surgical margins (PSM) and sexual function recovery within 12 months relative to RRP in a recent meta-analysis and several comparative studies [5-7]. A study revealed its superiority in terms of biochemical recurrence rate (BCR) at 3 years (92.1% in RRP vs 96.8% in RARP) [8], the others did parallel BCR between the two procedures [4, 6]. Pathological and oncological outcomes including PSA-relapse and cancer-specific mortality has not been sufficiently investigated. On page 10, line 7; A propensity-based analysis in order to minimize treatment selection bias also proved that RARP was associated with fewer PSM (13.6% vs 18.3%; odds ratio: 0.70; 95% confidence interval, ) [5]. 4. Minor points that might be addressed: RRP and RARP should be spelled out in the abstract PSM similarly We spelled out retro pubic radical prostatectomy (RRP), robot-assisted radical prostatectomy (RARP), and biochemical recurrence (BCR) (On page 2). 5. P6ln38 "bun" = but? We have changed bun to but (On page 6, line 1).

4 6. Figure 1 should be fixed so that the dotted line is more easily visible for RRP. We have revised Figure 1 according to reviewer s kind advice. Reviewer 2 Comments 1. This is a study by Fujimura et al on the differences observed in a number of short and long term outcome measures in patients treated for prostate cancer either with Robot-assisted radical prostatectomy (RARP) or with retro pubic radical prostatectomy (RRP). The authors conclude that RARP has an overall advantage over RRP regarding biochemical recurrence based on PSA increase during the follow-up period after surgery. The most interesting finding of the study is that the although the group treated with RARP had more patients with advanced disease these patients did better that the group treated with RRP that had less patients with advanced disease. However, the study is not a randomized clinical trial. Therefore, there was no randomization of patients and there is a possible selection bias. Furthermore, several critical information are missing, especially regarding the experience of the surgeons treating the two groups. These facts make the results of this study rather weak. The following points describe these weaknesses in detail. Thank you for positive comments and suggestions. 2. Major points 1. Tables 1&2 clearly show that more patients with advanced disease were treated with RARP compared with the RRP group and that in general the two groups had significant differences. Since this creates a possible selection bias the authors need to analyze its possible impact on their results. One of the possibilities is that more experience prostate cancer surgeons, taking up more difficult cases, have advanced their skills to RARP, while urologists that choose RRP, do so because they are not so "specialized". The authors comment on such a possibility in the discussion (paragraph 2). Correction for surgeon's experience based on years of

5 practice or more importantly RARP and RRP operations performed ever or during the last 5-10 years could help resolve this issue. I agree with reviewer s concern. I have included the following sentence in Methods and discussed t selection bias in Discussion. On page 5, line 8; since RARP became covered by insurance in Japan in April, 2012 we have performed RARP for all patients with localized PC. On page 10, line 8; there were few possibilities for surgery selection bias because we completely switched from RRP to RARP after instigation of insurance coverage in Another possibility is the observed difference in Lymphovascular Invasion (LVI). More patients treated with RRP had Lymphovascular invasion (LVI) compared to the RARP group. Could this be another reason that more of these patients had biochemical recurrence? Recently, LVI has been reported to be an independent factor for adverse outcomes in prostate cancer (BJU Int Jul 19. doi: /bju.13594). In general, the authors need to perform a more rigorous analysis of all the possible factors that could have an effect on their results and conclusions. Thank you for your kind suggestion. We have performed multivariate analyses using lymphovascular invasion (ref.14) and perineural invasion (ref. 15) and revised Table 3. On page 9 line 10; Serum PSA and surgical procedure were selected for the multivariate analysis because significant correlations between RARP and factors, such as Gleason score, extra prostatic extension, lymphovascular invasion, peri neural invasion, PSM, and lymph node metastasis were observed. Lymphovascular invasion perineural invasion were added for the analysis according to previous study [14, 15]. Multivariate analysis showed that RARP (HR,

6 0.57), perineural invasion (HR, 1.81), and serum PSA level (HR, 1.64) were significant prognostic predictors. 4. Wilcoxon signed-rank sum test is probably not the best choice for the kind of analysis performed in the study. Data are not paired in any way and patients were not randomly assigned to a treatment group. I therefore suggest that all statistics are performed again with the help of a statistician. We actually used Wilcoxon rank sum test (unpaired analysis), but mistakenly described it as Wilcoxon signed-rank sum test in the Methods section. We sincerely apologize for the confusing description (On page 6, line 6). 5. Minor points. Several non standard abbreviation appear in the abstract. We have now spelled out retro pubic radical prostatectomy (RRP), robot-assisted radical prostatectomy (RARP), and biochemical recurrence (BCR) (On page 2). 6. Discussion p.11. "The PSM..." most of the paragraph is out of the focus of the rest of the manuscript. Because assessment of positive surgical margin is one of the unique points of the present study, we would like to keep the paragraph.

7 7. The "poor group" in Figure 1 legend should be corrected to "high risk group" Thank you for kind advice. We have corrected it.