CLOCK Randomized Clinical Trial
Alessandro Antonelli,* Luca Cindolo, Marco Sandri, Filippo Annino, Marco Carini, Antonio Celia,
Carlo D’Orta, Bernardino De Concilio, Maria Furlan, Valentina Giommoni, Manuela Ingrosso,
Andrea Mari, Gianluca Muto, Roberto Nucciotti, Angelo Porreca, Giulia Primiceri, Luigi Schips,
Francesco Sessa, Claudio Simeone, Alessandro Veccia and Andrea Minervini, on behalf of the
AGILE Group
From the Urology Unit, ASST Spedali Civili Hospital, Department of Medical and Surgical Specialties, Radiological Science, and Public Health, University of Brescia (AA, MF, CS, AV), Data Methods and Systems Statistical Laboratory, University of Brescia, Brescia (MS) and the Urology Units of D’Annunzio Hospital, University of Chieti, Chieti (LC, CD, MI, GP, LS), San Donato Hospital, Arezzo (FA, VG), Careggi Hospital, University of Florence, Florence (MC, AM, GM, FS, AM), San Bassiano Hospital, Bassano Del Grappa (AC, BDC), Policlinico of Abano, Abano Terme (AP) and Misericordia Hospital, Grosseto (RN), Italy
Purpose:We sought to identify predictive factors of the transition from off clamp to on clamp robotic partial nephrectomy following an intraoperative decision.
Materials and Methods: In the multicenter, randomized, prospective CLOCK
(CLamp vs Off Clamp the Kidney during robotic partial nephrectomy) trial 152 and 149 of the 301 patients with a localized renal mass were assigned to undergo off clamp and on clamp robotic partial nephrectomy, respectively. Surgery was done at a total of 7 referral institutions by 1 surgeon per institution. A localized renal mass was defined as having a R.E.N.A.L. (radius, exophytic/endophytic, nearness to collecting system or sinus, anterior/posterior, location relative to polar lines, hilar) score less than 10. Surgeons had similar experience with at least 100 previous robotic partial nephrectomies. All patients underwent a preoperative and a 6-month renal scan. The current study deals with one of the secondary end points of the trial, comparing cases finalized as clampless (off robotic partial nephrectomy group) with those which were converted (shift robotic partial nephrectomy group).
Results: Of the 152 patients randomized to off clamp 61 (40%) were shifted to
clamp with a median ischemia time of 15 minutes. In the shift robotic partial nephrectomy group the masses were larger (3.5 vs 2.2 cm) and more complex (R.E.N.A.L. score 7 vs 6). A significant association with transition was found for tumor diameter (OR 1.4) and the R.E.N.A.L. score continuously (OR 1.4) and when recoded in groups, including 4dno risk (referent OR 1), 5-6dlow risk (OR 1.8), 7-8dintermediate risk (OR 3.6) and 9 or greaterdhigh risk (OR 6.6). The shift robotic partial nephrectomy group had longer operative time, higher blood loss and increased performance of 2-layer renorrhaphy. No significant differ-ences were noted in postoperative complications or renal function after 6 months.
Conclusions:The transition from off to on clamp robotic partial nephrectomy is
associated with renal mass diameter and complexity. Under the specific condi-tions of the current trial no harm was related to this decision.
Key Words: kidney neoplasms, nephrectomy, robotic surgical procedures, surgical instruments, morbidity
Abbreviations and Acronyms
CLOCK[ CLamp vs Off Clamp the Kidney during robotic partial nephrectomy
eGFR[ estimated glomerular filtration rate
PN[ partial nephrectomy RAPN[ robot assisted PN R.E.N.A.L.[ radius, exophytic/ endophytic, nearness to collecting system or sinus, anterior/ posterior, location relative to polar lines, hilar
SIB[ surface-intermediate-base
Accepted for publication February 5, 2019. The corresponding author certifies that, when applicable, a statement(s) has been included in the manuscript documenting institutional review board, ethics committee or ethical review board study approval; principles of Helsinki Declaration were followed in lieu of formal ethics committee approval; institutional animal care and use committee approval; all human subjects provided written informed consent with guarantees of confidentiality; IRB approved protocol number; animal approved project number.
Supported by the AGILE Group.
No direct or indirect commercial, personal, academic, political, religious or ethical incentive is associated with publishing this article.
* Correspondence: Piazzale Spedali Civili No. 1, 25123 Brescia, Italy (telephone:þ39303995215; e-mail: alessandro_antonelli@me.com).
0022-5347/19/2021-0062/0 THE JOURNAL OF UROLOGY®
Ó 2019 by AMERICANUROLOGICALASSOCIATIONEDUCATION ANDRESEARCH, INC.
https://doi.org/10.1097/JU.0000000000000194 Vol. 202, 62-68, July 2019 Printed in U.S.A.
PARTIALnephrectomy is the gold standard treatment of technically resectable cT1 renal tumors.1,2 It provides oncologic outcomes comparable to those of radical nephrectomy but confers a survival advan-tage due to greater preservation of renal function.3,4 The robotic approach to PN is gaining popularity with respect to its open and laparoscopic counter-parts, providing more favorable perioperative and functional outcomes.5e9
Along with the baseline quality of the paren-chyma and the amount of healthy tissue sacrificed by resection and sutures the major modifiable factor responsible for the functional decrease after PN is ischemic insult secondary to artery
clamp-ing.10,11 Accordingly several alternatives have
been suggested, including delayed clamping, early unclamping and selective clamping at various de-grees up to the extreme of no clamping with favorable functional outcomes in cases of subopti-mal baseline renal function.12e14 However, this approach is generally reserved only for less com-plex masses because facing resection with the kidney perfused is technically more demanding and carries the risk of major bleeding.15Thus, this approach requires accurate case selection but the indication still remains mostly subjective and at-tempts at rationalization are sparse.16
A common practice is to attempt clampless resection and eventually proceed to clamping if needed. Although this approach is widespread, to our knowledge it has been unreported and the literature provides no data on the incidence of aborted off clamp procedures.
We report the analysis of a secondary end point of the CLOCK randomized clinical trial to identify predictors of transition in the clamping approach during ongoing clampless RAPN. We also assessed inherent morbidity.
MATERIALS AND METHODS
The CLOCK study (ClinicalTrials.gov NCT02287987) is a multicenter randomized, controlled trial performed by the AGILE Group (Italian Group for Advanced Laparo-Endoscopic Surgery), which opened recruitment in September 2014 and closed it in October 2018. The full protocol was recently published.17 The primary end point of the trial was the difference in renal function at 6 months, for which a minimal sample size of 202 cases was estimated.
Participating surgeons, who were directly involved in the trial design, conformed to a well-defined profile. They were 35 to 40 years old, educated in current Italian courses in medicine and urology, and experienced with renal laparoscopic surgery. Each had been involved in robotics since 2010 or 2011 with approximately 100 to 200 procedures per year as the first operator and at least 100 previous RAPNs (median 160).
Study approval was obtained from the Ethics Com-mittee (registration No. NP 1814). Patients who provided informed consent were randomly assigned in a 1:1 ratio to clamp or off clamp RAPN. The assignment was deter-mined by a web based system after the candidate was assessed as eligible. The system was used to gather all study information, which was accessible only to the trial statistician (MS).
Participants were recruited at outpatient clinics. Those eligible for study inclusion had normal coagulative function, preoperative eGFR greater than 60 ml/minute/1.73 m2, a normal contralateral kidney and a renal mass with a R.E.N.A.L. score of 10 or less.18We calculated eGFR by the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation.19Split renal function was
deter-mined by renal scintigraphy at baseline and 6 months after surgery. Comorbidities were summarized using the Charlson-Romano index.20Intraoperative bleeding severity was quantified on a scale of 0dno bleeding to 5dbleeding faster than could be removed by suction. Postoperative complications were classified according to the Clavien-Dindo system21 and the resection strategy was docu-mented by the SIB score.22,23
The protocol regulated surgical steps, requiring each arm to completely remove perinephric fat and perform suspension on a loop of the artery. In the on clamp arm tumor resection and inner renorrhaphy were mandatorily done using ischemia while in the off clamp group the ar-tery remained unclamped during the procedure. Preop-erative transarterial embolization and intraopPreop-erative controlled deep systemic hypotension were not allowed.
At closure the CLOCK trial had recruited 301 cases, including 149 on clamp and 152 off clamp, preponderantly at a total of 3 centers (Florence, Chieti and Brescia) indicated as high volume.
In the current study we investigate a secondary end point, that is the transition of the clamping approach in participants allocated to the clampless arm. Of the 152 cases randomized to clampless RAPN 61 (40%) were indeed intraoperatively converted to on clamp (the shift RAPN group). The remaining 91 cases (60%) were completed without hilar clamping (the off RAPN group). We compared preoperative features to identify transi-tion predictors, and intraoperative and postoperative data to assess inherent morbidity.
Categorical variables were summarized as the abso-lute and relative frequencies, and numerical variables are shown as the mean SD or the median and IQR as appropriate. We used the Kruskal-Wallis rank test and the Fisher exact test to compare medians and pro-portions, respectively, between the study groups. The association of clinical features with the shift from a clampless to a clamped procedure was investigated by binary logistic regression and measured as the OR. All tests were 2-sided with p <0.05 considered signifi-cant. All calculations were performed with StataÒ, version 15.0.
RESULTS
Baseline patient features were similar in the off and shift RAPN groups. Conversely tumor features were
significantly unbalanced as the shift RAPN group had larger (3.5 vs 2.2 cm) and more complex masses (R.E.N.A.L. score 7 vs 6, each p <0.001, supple-mentary table 1, https://www.jurology.com). Retro-peritoneal vs transRetro-peritoneal surgical access was also unbalanced with a significantly greater preva-lence of the transperitoneal approach in the shift RAPN group (89% vs 78%, p[ 0.047). Multivariate models including unbalanced preoperative features revealed that tumor diameter (OR 1.4, p[ 0.009) and the R.E.N.A.L. score (each unit OR 1.4, p[ 0.006) were independently associated with the transition from off to on clamp surgery (supplementary table 2, https://www.jurology.com).
Four risk classes were identified in a multivar-iate model with the R.E.N.A.L. score as a discrete variable, including no riskd R.E.N.A.L. score 4 (OR 1), low riskdscore 5-6 (OR 1.8, p [ 0.311), intermediate riskdscore 7-8 (OR 3.6, p [ 0.031) and high riskdscore 9 or greater (OR 6.6, p [ 0.019, supplementary table 2, https://www.jurology.com, and see figure).
In conversion cases intraoperative data showed significantly longer operative time, greater blood loss, longer suture time, greater adoption of 2-layer renor-rhaphy and hemostatic use. Median warm ischemia time in the shift RAPN group was 15 minutes (IQR 12e18). In cases finalized in clampless fashion there was higher insufflation pressure during resection.
The postoperative complication rate was similar in the off and shift RAPN groups (25.3% and 24.6%, respectively) and complications were generally low grade. Postoperatively transfusions were administered
in 4 of 91 (4.4%) vs 1 of 61 patients (1.6%) in the off vs shift RAPN groups (p not significant). Drainage time was longer for shift RAPN (3 vs 2 days, p [ 0.004) while time to discharge home was similar (see table). As shown by the SIB score, no difference was found in the pathological pT3a stage or the positive surgical margin rate according to the resection strategy (see table).
At baseline the off and shift RAPN groups had similar global renal function (eGFR 88.2 and 86.3 ml/minute/1.73 m2) and a similar ipsilateral scin-tigraphy contribution (48.6% and 47.5%, respec-tively, supplementary table 2, https://www.jurology. com). At 6 months in the off and shift RAPN groups the decreases in eGFR (e7.6 ande8.1 ml/minute/ 1.73 m2) and split renal function (e2.1% ande2.3%) were similar, as was 12-month eGFR (e7.5 and e8.9 ml/minute/1.73 m2, respectively). However, at 6 and 12 months we observed a twofold eGFR decrease of greater than 25% in converted cases, which was not statistically significant (see table).
DISCUSSION
The goal of the CLOCK trial was to provide high level evidence comparing on and off clamp ap-proaches to RAPN. The trial closed accrual at 48 months with 301 participants. Institutions and surgeons complied with a defined profile so that the panel of operators could be considered reasonably homogeneous. Furthermore, the trial was per-formed in a standardized surgical context with pa-tient selection and surgical steps regulated by the study design and instrumentation constrained by default due to monopoly. According to our intention these boundaries should have mitigated the impact of surgeon related factors on the study end point, allowing reliable identification of the role of tumor related factors.
The conditions presented can be generalized to a relevant number of contemporary robotic in-stitutions but it must be acknowledged that the experience or expertise of the different surgeons could have influenced whether the procedure was finalized in clampless fashion. Nonetheless, our findings would be equally useful to refine surgical planning to enable further identification of tumor features. Indeed, the unique clinical scenario of this trial indicates that the differences between the finalized and converted cases should be described granularly when clampless RAPN is or is not feasible, given that the average surgical experience is the same as that of the involved surgeons.
The first notable finding was that 40% of the masses with a R.E.N.A.L. score of 10 or less could not be effectively treated with a clampless proced-ure. This evidence supports the poor diffusion of this
approach15 and calls into question the claim that most cases could instead be approached by also omitting isolation of the artery.24
The comparison of finalized vs shifted cases demonstrated that conversion depended mainly on tumor complexity according to definite risk classes (R.E.N.A.L. score 4dno risk, 5-6dlow risk, 7-8dintermediate risk and 9 or greaterdhigh risk). Conversely patient features seemed not to be asso-ciated with the risk of shift and surgeon features were not evaluable because they were homogeneous as stated. The lack of differences between high and low volume centers corroborates this homogeneity, indicating that the case load was not influential among expert surgeons.
Other groups have reported that tumor complexity influences the possibility of performing off clamp RAPN. The most updated meta-analysis showed that off clamp RAPN was performed for less complex tumors at a weighted mean difference of e0.29 and e1.30 for the R.E.N.A.L. score and the PADUA (Preoperative Aspects and Dimensions Used for
Anatomical) score, respectively.25 The correlation between anatomical complexity and the finalization of clampless RAPN adds the R.E.N.A.L. score as a new application during surgical planning. Clearly also other systems could equally or even better fulfil this role, given the limitations of the R.E.N.A.L. score also reported by our group.26
Another original finding was that in progress transition of the clamping approach did not imply additional morbidity. Accordingly a clampless approach could be safely attempted and eventually converted. However, it should be remarked that specific safety standards were observed, such as suspending the artery and dissecting all perinephric fat before resecting the tumor, so that the transition did not require additional maneuvers. Nevertheless, converted cases were probably more troublesome, as denoted by longer operative time, higher blood loss, more complex renorrhaphy, greater use of hemo-static agents and longer drainage time. The current study definitely indicates that the transition to clamping might also be accurately planned.
Intraoperative and perioperative course of patients randomized to off clamp partial nephrectomy who ultimately underwent unclamped procedure (off RAPN) vs those shifted to procedure requiring artery clamping (shift RAPN)
Off RAPN Shift RAPN p Value
No. pts 91 61 e
Intraopfindings
No. access (%): 91 61 0.047
Transperitoneal 71 (78.0) 54 (88.5)
Retroperitoneal 20 (22.0) 7 (11.5)
Median mins operative time (IQR) 115 (85e135) 130 (120e165) <0.001
Mean SD intra-abdominal pressure (mm Hg) 13.5 3.3 12.7 1.4 0.042
No. Airseal use/total No. (%) 67/90 (74.4) 45/61 (73.8) 1.000
Median cc estimated blood loss (IQR) 100 (50e150) 150 (80e250) 0.004
No. surgeon assessment of bleeding severity/total No. (%): 0.533
Minor (grade 0e2) 71/91 (78.0) 46/60 (76.7)
Major (grade 3e5) 20/91 (22.0) 14/60 (23.3)
No. hemostatic agent/total No. (%) 69/91 (75.8) 54/61 (88.5) 0.059
Mean SD suture time (mins) 9.3 4.8 11.7 4.9 0.001
No. renorrhaphy (%): 91 61 0.001 None 3 (3.3) 0 Medullary only 13 (14.3) 0 Cortical only 16 (17.6) 4 (6.6) Medullary D cortical 59 (64.8) 57 (93.4) Postop course
No. Clavien-Dindo complication grade (%): 91 61 0.602
1e2 20 (22.0) 15 (24.6)
3 or Greater 3 (3.3) 0
Median days drain removal (IQR) 2 (2e3) 3 (2e3) 0.004
Median days length of stay (IQR) 4 (3e4) 4 (3e5) 0.115
Pathologyfindings
No. total surface-intermediate-base score/total No. (%): 0.258
Enucleation (0e2 points) 61/88 (69.3) 38/59 (64.4)
Enucleoresection (3e4 points) 25/88 (28.4) 16/59 (27.1)
Resection (5 points) 2/88 (2.3) 5/59 (8.5)
No. pT3a/total No. (%) 6/88 (6.8) 1/57 (1.7) 0.246
No. pos surgical margins/total No. (%) 3/86 (3.5) 2/61 (3.5) 1.000
Functional outcomes 6-Mo eGFR change:
Mean SD ml/min e7.6 13.6 e8.1 15.0 0.749
% Greater than 25% 11.5 20.0 0.264
Mean SD % ipsilat scintigraphic function change e2.1 10.1 e2.3 10.9 0.575
12-Mo eGFR change:
Mean SD ml/min e7.5 16.0 e8.9 16.9 0.696
The off RAPN group had a less pronounced im-mediate reduction in eGFR (data not reported) and a lower rate of a relevant (greater than 25%) func-tional decrease at followup, although ultimately no significant difference emerged in functional results. Nonetheless, it should be highlighted that this equivalence in functional outcome cannot be trans-lated to the comparison between the off and on clamp approaches for several reasons. The clamping strategy in converted cases was variable, rather resembling ultra delayed clamping. The groups differed in tumor features related to the quantity of parenchyma sacrificed. Finally, no specific sample size calculation was done on this end point. An incoming study of the primary end point of the CLOCK trial will be dedicated to this issue.
Originally in the current study we relied on a standardized and validated system to report the resection strategy, ie the SIB score.22,23 Unexpect-edly the conversion rates after enucleoresection and enucleation were similar, although the enucleation strategy should provide the benefit of a bloodless dissection plan and consequently should be less prone to the need for artery clamping.27
The possibility of improving the strategy of the clamping approach could be relevant in specific clinical scenarios. 1) Expert surgeons could identify no or low risk cases for which artery preparation could be omitted. 2) Conversion could be accurately planned with the surgical team in high risk cases.
3) Alternative approaches such as selective clamp-ing, open PN and ablative techniques could be considered in patients at high risk and those in whom it is mandatory to avoid ischemia.
The current study has several limitations which must be acknowledged, including 1) the small cohort size, although it is comparable to that in major reported experiences on clampless RAPN; 2) the bias due to surgeon preference notwith-standing our efforts; 3) the lack of an assessment of difficult perinephric fat dissection even if such surrogates as patient age, gender and body mass index were equally distributed in finalized and converted cases; and 4) the lack of volumetric assessment to evaluate whether transition influ-enced the quantity of sacrificed parenchyma and renal function.28
CONCLUSIONS
Off clamp RAPN is a challenging procedure in which feasibility depends on the anatomical complexity of the tumor. The attempt to perform an off clamp approach and subsequent intraoperative conversion to a clamped procedure seems not to be harmful when the pedicle has been preliminarily prepared. At any rate correct planning could favor surgeon com-fort and in turn the achievement of the major goals of PN, which are no tumor violation, perfect hemostasis and an uneventful postoperative course.
REFERENCES
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2. Campbell SC, Novick AC, Belldegrun A et al: Guideline for management of the clinical T1 renal mass. J Urol 2009;182: 1271.
3. Wang Z, Wang G, Xia Q et al: Partial nephrec-tomy vs. radical nephrecnephrec-tomy for renal tumors: a meta-analysis of renal function and cardiovas-cular outcomes. Urol Oncol Semin Original Invest 2016;34: 533.e11.
4. Antonelli A, Minervini A, Sandri M et al: Below safety limits, every unit of glomerular filtration rate counts: assessing the relationship between renal function and cancer-specific mortality in renal cell carcinoma. Eur Urol 2018;74: 661. 5. Mari A, Antonelli A, Bertolo R et al: Predictive
factors of overall and major postoperative com-plications after partial nephrectomy: results from a multicenter prospective study (The RECORd 1 project). Eur J Surg Oncol 2017;43: 823. 6. Antonelli A, Mari A, Longo N et al: Role of
clinical and surgical factors for the prediction of immediate, early and late functional results, and
its relationship with cardiovascular outcome after partial nephrectomy: results from the pro-spective multicenter RECORd 1 project. J Urol 2018;199: 927.
7. Shen Z, Xie L, Xie W et al: The comparison of perioperative outcomes of robot-assisted and open partial nephrectomy: a systematic review and meta-analysis. World J Surg Oncol 2016;14: 220.
8. Schiavina R, Mari A, Antonelli A et al: A snap-shot of nephron-sparing surgery in Italy: a pro-spective, multicenter report on clinical and perioperative outcomes (the RECORd 1 project). Eur J Surg Oncol 2015;41: 346.
9. Ghani KR, Sukumar S, Sammon JD et al: Practice patterns and outcomes of open and minimally invasive partial nephrectomy since the intro-duction of robotic partial nephrectomy: results from the nationwide inpatient sample. J Urol 2014;191: 907.
10. Thompson RH, Lane BR, Lohse CM et al: Every minute counts when the renal hilum is clamped during partial nephrectomy. Eur Urol 2010; 58: 340.
11. Thompson RH, Lane BR, Lohse CM et al: Renal function after partial nephrectomy: effect of warm ischemia relative to quantity and quality of preserved kidney. Urology 2012;79: 356. 12. Kaczmarek BF, Tanagho YS, Hillyer SP et al:
Off-clamp robot-assisted partial nephrectomy preserves renal function: a multi-institutional propensity score analysis. Eur Urol 2013;64: 988.
13. Rosen DC, Paulucci DJ, Abaza R et al: Is off clamp always beneficial during robotic partial nephrectomy? A propensity score-matched com-parison of clamp technique in patients with two kidneys. J Endourol 2017;31: 1176.
14. Peyronnet B, Khene Z-E, Pradere B et al: Off-clamp versus on-Off-clamp robotic partial nephrec-tomy: a multicenter match-paired case-control study. Urol Int 2017;99: 272.
15. Simone G, Gill IS, Mottrie A et al: Indications, techniques, outcomes, and limitations for mini-mally ischemic and off-clamp partial nephrec-tomy: a systematic review of the literature. Eur Urol 2015;68: 632.
16. Li Y, Zhou L, Bian T et al: The zero ischemia index (ZII): a novel criterion for predicting complexity
and outcomes of off-clamp partial nephrectomy. World J Urol 2017;35: 1095.
17. Cindolo L, Antonelli A, Sandri M et al: The role of vascular clamping during robot-assisted partial nephrectomy for localized renal cancer: rationale and design of the CLOCK randomized phase III study. Minerva Urol Nefrol 2019;71: 96. 18. Kutikov A and Uzzo RG: The R.E.N.A.L.
nephrom-etry score: a comprehensive standardized system for quantitating renal tumor size, location and depth. J Urol 2009;182: 844.
19. Levey AS and Stevens LA: Estimating GFR using the CKD epidemiology collaboration (CKD-EPI) creatinine equation: more accurate GFR esti-mates, lower CKD prevalence estiesti-mates, and better risk predictions. Am J Kidney Dis 2010;55: 622.
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22. Minervini A, Carini M, Uzzo RG et al: Standard-ized reporting of resection technique during nephron-sparing surgery: the surface-intermedi-ate-base margin score. Eur Urol 2014;66: 803. 23. Antonelli A, Furlan M, Sodano M et al: External
histopathological validation of the surface-inter-mediate-base margin score. Urol Oncol Semin Original Invest 2017;35: 215.
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28. Klingler MJ, Babitz SK, Kutikov A et al: Assessment of volume preservation performed before or after partial nephrectomy accurately predicts postoperative renal function: results from a prospective multicenter study. Urol Oncol 2019;37: 33.
EDITORIAL COMMENTS
The authors present a randomized trial on the controversial topic of the possible functional benefit of off clamp RAPN. This report focuses on a sec-ondary outcome and the primary outcome will be reported later.
Of the cases of the planned off clamp approach performed by 7 experienced surgeons, each with more than 100 RAPNs, 40% required an intra-operative shift to on clamp. Tumor diameter and the R.E.N.A.L. score predicted the shift and these cases had greater blood loss and operative time. There was no difference in postoperative complications or importantly in renal function at 6 months. A recent meta-analysis showed a renal function benefit for off clamp RAPN but the study was limited by the quality of source data (reference 25 in article).
The learning curve is difficult to define and can differ among surgeons and by the parameter assessed.1 A 40% shift rate may be too high for a highly experienced surgeon and yet too low for a
novice. Most RAPNs at nontertiary centers are done by surgeons with less experience and a lower case volume. We applaud the effort to advance science but urge caution until there is robust evidence of lasting benefit of off clamp RAPN, which in less experienced hands could lead to an adverse outcome.
At the time of this writing we believe that the majority of surgeons should clamp the artery (and sometimes also the vein), perform meticulous tumor excision under excellent visualization and recon-struct the kidney securely with a reasonably short ischemia time in a manner that is comfortable for the individual surgeon. This should achieve the most important goals of no tumor violation, perfect hemostasis and functional preservation.
John Graham, Jr. and Monish Aron
University of Southern California Los Angeles, California
REFERENCE
1. Larcher A, Muttin F, Peyronnet B et al: The learning curve for robot-assisted partial nephrectomy: impact of surgical experience on perioperative outcomes. Eur Urol 2019; 75: 253.
As RAPN gradually takes over as the current gold standard of nephron sparing surgery, the on/off clamp debate remains alive, stimulating the
discussion between adopters of one or the other approach.1 Regardless of the study findings, the CLOCK trial is a commendable effort (reference 17
in article). Trying to answer a clinical question by a randomized clinical trial is the target at which we should always aim as researchers but most of the time this represents a prohibitive task.2 In this study the authors found that the more complex the tumor, the more likely the surgeon is forced to clamp after starting off clamp. They also found that starting the procedure off clamp with possible con-version to on clamp can be a safe plan, given that certain precautions are taken such as renal artery dissection and isolation for a quick conversion.
Unfortunately we are afraid that the debate will not end here. As in other procedures, the surgical
strategy during robotic PN is surgeon driven. Meanwhile we should keep in mind that limiting ischemia is certainly important (especially in pa-tients with baseline compromised renal function) but it is even more important to get a negative margin, minimize parenchymal loss and avoid complications. These are the pillars of a well per-formed RAPN.
William Visser and Riccardo Autorino
Division of Urology Virginia Commonwealth University Health System Richmond, Virginia
REFERENCES
1. Greco F, Autorino R, Altieri V et al: Ischemia techniques in nephron-sparing surgery: a systematic review and meta-analysis of surgical, oncological, and functional outcomes. Eur Urol 2019;75: 477.
2. Catto JW, Blazeby JM, Holmberg L et al: In defense of randomized clinical trials in surgery: let us not forget Archie Cochrane's legacy. Eur Urol 2017;71: 820.
REPLY BY AUTHORS
We appreciate the comments on our CLOCK trial study (reference 17 in article). We agree that the choice to change the clamping approach largely de-pends on surgeon attitude and experience. The transition rate in our study seems notably high at 40% but to our knowledge this information was never reported before and no comparisons with previous experiences were possible.
Nevertheless, besides surgeon related factors, 2 other reasons could explain why the off clamp approach was so frequently abandoned. 1) The permissive inclusion criteria of the study (R.E.N.A.L. score 10 or less and any diameter) allowed for randomization to off clamp PN for masses generally deemed not amenable to this approach. The risk of conversion was indeed
related exclusively to tumor diameter and complexity. Others have reported that the recourse to a clampless procedure is marginal for larger masses.1 2) Robotic systems provide enhanced vision which can be a disadvantage if bleeding occurs. With the lack of haptic feedback it may force surgeons to choose clamping to restore clean vision. Hopefully the data from the CLOCK2 trial, which is identical in design but enrolls only purely laparoscopic procedures, could contribute to test this hypothesis through an in-direct comparison.
Finally, it was notable that the outcomes of con-verted and finalized cases overlapped, reasserting that warm ischemia is only one of the factors responsible for functional damage after PN.2
REFERENCES
1. Bertolo R, Autorino R, Simone G et al: Outcomes of robot-assisted partial nephrectomy for clinical T2 renal tumors: a multicenter analysis (ROSULA Collaborative Group). Eur Urol 2018;74: 226.
