Purely Off-Clamp Laparoscopic Partial Nephrectomy Stands the Test of Time: 15 Years Functional and Oncologic Outcomes from a Single Center Experience

Round 1

Reviewer 1 Report

I have read the submitted manuscript with great interest. The retrospective study evaluates functional and oncological outcomes in patients who underwent off-clamp laparoscopic partial nephrectomy. The study also presents long-terms, 15 years, outcomes.

I would like to determine my thoughts about the manuscript as follows,

1-     The study includes the patients who underwent LPN by using off- clamp technique, therefore please select a more relevant title for the manuscript.

2-     Could you please determine the time interval in more detail etc. from .... to .....

3-     Who or who carried out the operations? Is it a single surgeon outcome?

4-     Did any patient need a conversion to an on-clamp technique or radical nephrectomy?

5-     Randomized Clinical Trial Comparing On-clamp Versus Off-clamp Laparoscopic Partial Nephrectomy for Small Renal Masses (CLOCK II Laparoscopic Study): A Intention-to-treat Analysis of Perioperative Outcomes. doi: 10.1016/j.euros.2022.10.007  This study may be helpful for the discussion section.

6-     The complexity of the renal tumor, tumor size, localization, and surgeon experience might affect the decision of laparoscopic partial nephrectomy technique. Why did the authors not use the renal nephrometry score to indicate the tumor complexity?

7-     To evaluate functional outcomes correctly, I suggest the authors include more homogenous cohorts such as patients with normal contralateral functioning kidneys. Patients with solitary kidneys might affect long-term functional results.

 

Sincerely,

Author Response

1. The study includes the patients who underwent LPN by using off- clamp technique, therefore please select a more relevant title for the manuscript.

We thank the reviewer for the suggestion.

The title was modified accordingly:

• (Title, pg 1, lines 2-4): Purely off-clamp laparoscopic partial nephrectomy stands the test of time: 15 years functional and oncologic outcomes from a single center experience

 

2. Could you please determine the time interval in more detail etc. from .... to .....

We thank the reviewer for the suggestion.

The study timeframe was better clarified:

• (Abstract, pg 1, lines 13-14): a retrospective analysis was performed on patients who underwent ocLPN between May 2001 and December 2005
• (Materials and Methods, pg 2, lines 52-54): After institutional review board approval, our prospectively maintained database was queried for patients undergone LRP for organ-confined (cT1-2N0M0) renal tumors, between May 2001 and December 2005.

 

3. Who or who carried out the operations? Is it a single surgeon outcome?

We thank the reviewer for the question.

We totally agree with him/her that it is worth clarifying that our data are based on a single-center single-surgeon experience:

• (Materials and Methods, pg 2, lines 79-81): An off-clamp approach was always attempted. The surgical technique has been previously described elsewhere [12,13]. All the surgeries were performed by a single experienced surgeon (M.G.)

Indeed, this is among the main limitations of our study and it was acknowledged in the dedicated section of the Discussion.

• (Discussion, pg 8, lines 208-210): Second, the study population was limited and only representative of a single-surgeon, single high-volume center experience: therefore, results herein reported may be difficult to generalize

 

4. Did any patient need a conversion to an on-clamp technique or radical nephrectomy?

We thank the reviewer for the question.

We definitely agree with the reviewer that it is relevant clarifying that we recorded no case of intraoperative conversion to on-clamp or radical nephrectomy.

• (Results, pg 3, lines 104-105): All the treated patients underwent a purely off-clamp approach, and no case of intraoperative conversion to radical nephrectomy was observed.

 

5. Randomized Clinical Trial Comparing On-clamp Versus Off-clamp Laparoscopic Partial Nephrectomy for Small Renal Masses (CLOCK II Laparoscopic Study): A Intention-to-treat Analysis of Perioperative Outcomes. doi: 10.1016/j.euros.2022.10.007  This study may be helpful for the discussion section.

We thank the reviewer for the suggestion.

We totally agree with him/her that conflicting results were found when comparing functional outcomes of on-clamp and off-clamp partial nephrectomy: while several single/multicenter studies described a significant advantage of the latter in terms of post-operative renal function preservation, the well-known CLOCK trial failed to prove any superiority.

These evidences were also reported in the discussion section, to offer the reader a reliable idea of the current body of the literature concerning this topic.

• (Discussion, pg 7, lines 159-180): Clamping of the renal hilum is traditionally performed during PN to minimize intraoperative blood loss and enhance visualization of the surgical field. Every minute of warm ischemia may increase the risk of post-operative renal function deterioration[22], although conflicting evidence was reported concerning this topic. Two recent RCTs found no difference in functional outcomes between on- vs off-clamp approaches[23,24]: most of enrolled patients, however, presented with low-nephrometry renal masses and, consequently, short average warm ischemia times were observed in the on-clamp arms. Conversely, we proved that WIT does affect postoperative renal function and this can be easily observed in patients with a solitary kidney (which cannot rely on a contralateral healthy organ to cope with the surgical injury)[25–27] and large renal tumors (that usually require > 20 minutes of WITs)[28]. Laparoscopy is usually associated with longer warm ischemia time, compared to open and robotic surgery[29]. With this regard, Lane et al demonstrated that patients with a solitary kidney undergoing LPN are at higher risk of postoperative dialysis (10% vs 0.6%; p=0.001) that those treated with an open PN[26]. The off-clamp technique avoids ischemic injury[30] and proved, both in the imperative[31] and in the elective settings[32], to better preserve post-operative renal function. The trade-off, however, is the increased intraoperative bleeding[30] which could jeopardize positive surgical margins rate. In the present series, this rate (5%) remained in line with that from other large laparoscopic and open series (0.3%-7%)[29] and, at 15 years follow-up, 7 patients (11%) were diagnosed with newly onset CKD stage IIIa while 2 (3%) developed a stage IV. Comparable functional results were observed in other PN cohorts, regardless the open, laparoscopic or robotic approach[33].

 

6. The complexity of the renal tumor, tumor size, localization, and surgeon experience might affect the decision of laparoscopic partial nephrectomy technique. Why did the authors not use the renal nephrometry score to indicate the tumor complexity?

We thank the reviewer for the comment.

Actually, the most widely accepted nephrometry scales had not been conceived yet at the time of our study: in fact, both the RENAL (10.1016/j.juro.2009.05.035) and PADUA (10.1016/j.eururo.2009.07.040) scores were proposed in 2009. For this reason, we are unable to provide the reader with data comprehensively representing the surgical complexity of the treated tumors.

Nonetheless, we already disclosed that most of patients included in our study presented with small renal masses (75% pT1a): considering that those were the pioneering days of LPN, it is not surprising that mostly uncomplex tumors were considered eligible for a minimally-invasive approach.

• (Discussion, pg 8, lines 213-216): Another limitation lies in the fact that only a quarter of the enrolled patients presented with a ≧ T1b tumor. Although there is increasing evidence that a minimally invasive PN is a valuable treatment option in selected cases, most of the published series from that era share the same median tumor size.

 

7. To evaluate functional outcomes correctly, I suggest the authors include more homogenous cohorts such as patients with normal contralateral functioning kidneys. Patients with solitary kidneys might affect long-term functional results.

We thank the reviewer for his/her suggestion.

We well know that the latters represent a special population, as they cannot rely on a contralateral functioning organ to cope with the surgical injury suffered by the treated kidney at the time of partial nephrectomy. For this reason, functional outcomes observed in this specific subset of patients are difficult to generalize. However, only 3/63 (4%) patients included in our study presented with a solitary kidney so that their impact on the results of our analysis is negligible. On the other hand, considering the exiguity of our sample, excluding patients from the analysis should be avoided if not strictly required.

Author Response File: Author Response.pdf

Reviewer 2 Report

Given the big amount of data on the topic in the current literature, the real value of the manuscript is the long follow-up. Indeed, the study aim is to report functional and oncologic outcomes after 15 years of off-clamp LPN (ocLPN) at our center. The manuscript is interesting but needs some extra work. 

- Please expand the introduction with current evidence including ablative technique as a variable option in the specific subset of patients you reported. Despite the nephron-sparing surgery represent the gold standard for organ-confined renal tumors ablative techniques are currently recognized by guidelines as safe NSS options. For the scope please cite the following paper which gives an up-to-date multi-institutional mature experience even in challenging scenarios comparing surgery vs ablative techniques (DOI: 10.1016/j.ejso.2022.09.022- PMID: 36216659) (DOI: 10.1089/end.2022.0478 - PMID: 36367175)

- I suggest splitting the table for baseline characteristics and for outcomes. Table one should be for baseline characteristics and table 2 for LPN outcomes.

- Whit regard to the suggested Table 1. If possible, please add some important missing information such as hypertension rate, diabetes, ASA score, and any nephrometry score to better describe humor complexity such as RENAL or PADUA.

- Whid regards to the suggested Table 2. If possible, please add some important missing information such as operative time, Hb drop, and length of stay.

- What about complications? did you not record anyone?

- As a composite Onco-functional outcome you reported ROMeS. why did you not consider reporting the top-ranked Trifecta? Moreover, the citation n 15 which you reported should be re-evaluated as it seems not specific.   

- You reported an analysis to report predictors for ROMeS achievement. As a variable, you considered benign vs malignant histology. This is incorrect because ROMeS itself is defined as the absence of recurrence and only malignant histology should be considered in the analysis. Please correct this point.

- check typos 

Author Response

1. Please expand the introduction with current evidence including ablative technique as a variable option in the specific subset of patients you reported. Despite the nephron-sparing surgery represent the gold standard for organ-confined renal tumors ablative techniques are currently recognized by guidelines as safe NSS options. For the scope please cite the following paper which gives an up-to-date multi-institutional mature experience even in challenging scenarios comparing surgery vs ablative techniques (DOI: 10.1016/j.ejso.2022.09.022- PMID: 36216659) (DOI: 10.1089/end.2022.0478 - PMID: 36367175).

We thank the reviewer for the suggestion.

We totally agree with him/her that percutaneous thermal ablation (PTA) techniques represent a viable option to treat renal tumors and should be considered especially in case of frail patients with masses < 3cm. We also well know that, in this specific setting, PTA provided surgical and functional outcomes comparable to those of robotic partial nephrectomy, as recently reported by Pandolfo and colleagues. Accordingly, we modified the first lines of the discussion section, to provide the reader with a concise overview of the currently available strategies to treat renal tumors. Both the suggested papers were cited.

• (Discussion, pg 6, lines 142-147): International guidelines recommend NSS whenever feasible, and mostly to treat cT1 renal tumors. Although percutaneous thermal ablation techniques represent a viable option and should be considered in case of frail patients with small (<3 cm) masses[14,15], PN is nowadays considered the gold standard for organ-confined diseases[2] and, with the introduction of the robotic surgical platforms, it can be also offered to selected patients with large neoplasms[16].

 

2. I suggest splitting the table for baseline characteristics and for outcomes. Table one should be for baseline characteristics and table 2 for LPN outcomes.
3. Whit regard to the suggested Table 1. If possible, please add some important missing information such as hypertension rate, diabetes, ASA score, and any nephrometry score to better describe humor complexity such as RENAL or PADUA.
4. Whit regards to the suggested Table 2. If possible, please add some important missing information such as operative time, Hb drop, and length of stay.
5. What about complications? did you not record anyone?

We thank the reviewer for comments and suggestions.

As recommended, Table 1 was split into two different tables: the first shows baseline characteristics of the study population (and we added info concerning hypertension, diabetes and ASA score) while the second displays outcomes after LPN. Although describing perioperative outcomes of off-clamp LPN was beyond the aim of the present study, according to the reviewer’s suggestion we reported LOS and Hb drop in Table 2, and we concisely described our complication rate direcly in the Results section of the manuscript.

Regarding nephrometry scores, it must be considered that both the RENAL (10.1016/j.juro.2009.05.035) and PADUA (10.1016/j.eururo.2009.07.040) scores were proposed in 2009: for this reason, these were not calculated at the time of surgery and we are unable to provide the reader with data comprehensively representing the surgical complexity of the treated tumors.

• (Results, pg 3, lines 106-110): Median LOS was 5 (IQR: 3-6) days (Table 2) and 12 patients overall required blood transfusion (6 in both groups; p=0.65); no severe recurrences requiring surgery or intensive care unit admission were observed (data not shown). All the treated patients underwent a purely off-clamp approach, and no case of intraoperative conversion to radical nephrectomy was observed.

Moreover, we included Hypertension, Diabetes and ASA score in our Cox regression analysis to identify predictors of ROMeS non-achievement (Table 3).

 

6. As a composite Onco-functional outcome you reported ROMeS. why did you not consider reporting the top-ranked Trifecta? Moreover, the citation n 15 which you reported should be re-evaluated as it seems not specific.

We thank the reviewer for the comment.

We well known that several composite outcomes were proposed to report results after partial nephrectomy. Actually, the MIC (Margin, ischemia and complications) is a useful clinical tool, which however implies hilar clamping as mandatory surgical step [Urology 2015;85:589–95], thus limiting its applicability to the on-clamp approach only. The trifecta as proposed by Hung et al is impractical as requires a volumetric imaging assessment with a subjective estimation of the preserved renal pa- renchyma [10.1016/j.juro.2012.09.042].

To help standardizing early outcomes reporting, we recently published a reproducible and widely applicable Trifecta [10.23736/S0393-2249.19.03570-7]

However, the true goal of nephron sparing surgery (nSS), is providing a durable cancer control while preserving a sufficient renal function and ensuring a long-life expectancy. Therefore, we also defined a new triad (that we called ROMe’s) of main long-term clinical outcomes after PN (no Recurrences, no Overall Mortality and absence of estimated glomerular filtration rate significant reduction).

 

 

7. You reported an analysis to report predictors for ROMeS achievement. As a variable, you considered benign vs malignant histology. This is incorrect because ROMeS itself is defined as the absence of recurrence and only malignant histology should be considered in the analysis. Please correct this point.

We thank the reviewer for the comment.

Generally speaking, what actually differentiate a benign tumor from a malignancy is the capability of the latter of invading the neighboring organs and/or metastasize (https://training.seer.cancer.gov/disease/cancer/terms.html). In fact, although rarely, benign (kidney) tumors can recur [10.1097/00005392-199907000-00010] [10.3892/mco.2018.1755].

Moreover, our definition of “recurrence” also included metachronous renal masses (even carcinomas) affecting the ipsi-/contralateral kindey: this circumstance is not uncommon indeed.

For these reasons, we believe that it is not mistaken assessing the association between malignant histologies and ROMeS probabilities: as expected, in fact, kidney cancers are inversely associated with the chances of achieving our composite favorable outcome.

 

1. check typos

We thank the reviewer for the suggestion.

The manuscript was carefully reviewed by a native English speaker.

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

I have read the manuscript one more time, and the authors have replied with suggestions. To me, the manuscript may be considered for publication.

Reviewer 2 Report

The manuscript has been deeply improved after the first round. a have appreciated the improvement in the result presentation and table implementation. I believe it is worthy of publication.

Of note: if you find it important to complete the topic you brilliantly discussed on RFA, please include this interesting paper as cit. on a novel approach vs standard (DOI: 10.23736/S2724-6051.22.05092-3)

the authors should be congratulated for the interesting topic