Li Lin Kun , , , Christopher P Nel , Vux Roertson , Michel Jones ,Ashley R Dennison , Giuseppe Grce

a Department of Hepatobiliary and Pancreatic Surgery, Leicester General Hospital, University Hospitals of Leicester NHS Trust, Gwendolen Road, Leicester LE5 4PW, UK

b Discipline of Surgery, The Queen Elizabeth Hospital, The University of Adelaide, Adelaide, South Australia, Australia

TotheEditor:

The Pringle maneuver (PM) was initially described more than a century ago to control bleeding associated with hepatic trauma and it remains the most common method to block hepatic inflow and minimize blood loss during hepatic resections [1] . The potential effects of ischemia-reperfusion injury (IRI), a consequence of the PM, on the function of the liver remnant remain controversial [2] . Pre-clinical data have suggested that IRI may potentiate the growth of metastatic colorectal cells [3] , raising concerns regarding long-term oncological outcomes associated with use of the PM. Several large clinical studies involving patients undergoing resections for colorectal liver metastases (CRLM) have shown no significant differences in survival or hepatic recurrence regardless of whether the PM is used [ 4 , 5 ]. However, there remain concerns whether the PM may influence long-term oncological outcomes.

Traditionally, a tumor free (R0) resection margin of at least 1 cm was recommended for CRLM resections. It is now evident that smaller resection margins, even submillimeter margins, improve survival [6] . Due to vascular proximity or multinodularity,complete macroscopic resection can sometimes only be performed through R1 resection. Microscopically positive resection margins is a prognostic factor in the recurrence of CRLM. Intrahepatic recurrences are significantly associated with microsatellite metastases around the main metastatic tumor [7] . Histopathological growth patterns describe the distinct interface between the border of CRLM and the normal liver parenchyma and have been standardized by international consensus guidelines as they impact overall survival after hepatic resection for CRLM [8] . This study aimed to assess whether the use of the PM may adversely affect oncological outcomes in patients undergoing hepatic resection for CRLM.

All patients who underwent a hepatic resection for CRLM in the University Hospitals of Leicester NHS Trust between May 2001 and August 2012 were identified from a contemporaneously maintained data set. The exclusion criteria were patients who underwent ablation, either alone or in combination with hepatic resection, and those with macroscopically positive resection margins (R2). Where patients had undergone multiple hepatic resections, only the first procedure was included in the analysis. R1 resection was defined as tumor demonstrated within 1 mm of the resection margin.

All patients had preoperative radiological staging, which included thoracic, abdominal and pelvic CT scans. Staging laparoscopy was performed selectively. PET-CT was introduced into the unit protocol as a routine staging investigation prior to hepatic resections. Decisions regarding the administration of systemic chemotherapy and its timing in relation to surgery were made in conjunction with the medical oncologists at the regional hepatobiliary multidisciplinary team meeting.

An intermittent PM was utilized at the discretion of the operating surgeon. Cycles consisted of an occlusion time of 10 minutes,followed by a 5-minute clamp free period throughout parenchymal transection. No alternative clamping method was utilized in patients who did not have the PM. Hepatic resections were performed using the Cavitron Ultrasonic Surgical Aspirator (Integra LifeSciences Corp., Princeton, NJ, USA). Patients were initially reviewed at 1 month following surgery. Follow-up then consisted of outpatient visits, along with measurement of carcinoembryonic antigen and a surveillance CT scan at an interval of six months for the first two years, then annually for the subsequent three years.Recurrence was defined as intra- or extrahepatic lesion(s) that deemed suspicious on cross-sectional imaging or biopsy-proven adenocarcinoma. The primary outcomes measured were overall survival; defined as the interval between time of hepatic resection to time of death, and disease-free survival; defined as the interval between the time of hepatic resection to time of recurrence. The secondary outcome was disease recurrence.

Groups were compared using the unpairedt-test, Mann-WhitneyUtest and Chi-square test, as appropriate. The Spearman test was used to assess correlation between two continuous variables. Overall and disease-free survivals were analyzed using the Kaplan-Meier method and survival curves were compared using the log-rank test. All statistical analyses were performed usingSPSS? for Mac? version 24 (SPSS, Chicago, IL, USA). AP＜0.05 was considered statistically significant.

During the study period, R0 and R1 resections for CRLM were reported in 238 and 98 patients, respectively. A PM was utilized in 117 patients (49%) who underwent an R0 resection and in 58(59%) who underwent an R1 resection. Tables 1 and 2 summarize key clinicopathological features of patients who underwent R0 and R1 hepatic resections with reference to application of a PM. A PM was not associated with any statistically significant differences between patients who underwent either R0 or R1 resections with respect to demographics, tumor-related factors, operation-related factors or the use of chemotherapy.

Following an R0 resection, recurrent liver metastases developed in 55 patients (47%, 55/117) in whom a PM was utilized and in 60(50%, 60/121) whose resection did not involve a PM (P= 0.691).Hepatic recurrence following an R1 resection occurred in 43 (74%,43/58) and 23 (58%, 23/40) patients in the PM and no PM cohorts,respectively (P= 0.084). In patients who had undergone R1 resections, there was no significant correlation between the total Pringle time and the time to hepatic recurrence (r= 0.219,P= 0.221).

Disease recurrence at any site occurred in 80 patients (68%,80/117) who underwent an R0 resection with a PM and in 82 (68%,82/121) who underwent an R0 resection without a PM (P= 0.920).Comparable figures for disease recurrence following an R1 resection were 45 (78%, 45/58) and 31 (78%, 31/40) patients with and without use of a PM, respectively (P= 0.992).

Following an R0 resection with a PM the median censored disease-free survival was 19 (range 0-104) months, compared to 12 (range 0-94) months without a PM (P= 0.069). Comparable figures for an R1 resection, with and without a PM were 10 (range 1-7) months and 12 (range 0-117) months, respectively (P= 0.207).

The median censored overall survival in patients who underwent an R0 resection and had a PM was 39 (range 0-129) months,compared with 35 (range 0-97) months in those who did not have a PM (P= 0.212). Following an R1 resection median overall censored survival was 28 (range 1-70) months and 30 (range 0-186)months with and without a PM, respectively (P= 0.193) ( Fig. 1 ).

This study did not show any statistically significant differences in clinicopathological factors between patients who underwent hepatic resections with or without a PM. A PM was utilized in a greater proportion of patients who underwent R1 (59%), compared to R0 resections (49%), likely reflecting its increased use in more challenging resections. Of the 336 patients included in this series,98 patients (29%) underwent an R1 resection, consistent with the reported range of 9% to 49% [9] .

The potential effects of the PM in patients undergoing R1 resections for CRLM are uncertain. However, pre-clinical data have suggested that IRI may potentiate the growth of colorectal metastases leading to postulations that a similar affect could be associated with the PM [10] . A number of mechanisms have been proposed to account for IRI promoting tumor growth. After a hepatic resection, various molecules that promote regeneration are induced and/or secreted which activate non-parenchymal liver cells to produce a range of pro-inflammatory cytokines. Direct oxidative mitogenic stimuli, along with cytokines, promote proliferation.

The difference between rates of hepatic recurrence in patients who underwent R0 and R1 resections was sizeable, but it did not achieve statistical significance. To date, studies seeking to establish the long-term oncological outcomes associated with use of the PM in patients with CRLM have not evaluated the potential effects of resection margin status. These studies have shown that the PM is not associated with adverse effects on intrahepatic recurrence,overall and disease-free survivals [ 4 , 5 ]. However, a study which involved 2368 patients with hepatocellular carcinoma demonstrated that the application of PM longer than 15 minutes was associated with a higher rate of recurrent disease and lower recurrence-free and overall survivals [11] . Our data showed that median overall and disease-free survivals were both two months shorter in patients who had undergone an R1 resection with a PM. However,neither differences in outcome measure reached statistical significance. It was also observed that there was a relatively high proportion of metachronous and single CRLM in the patients included,however, the overall survival was relatively low in R0 group and we are unable to identify a cause for this.

The observation that R1 resections coupled with PM had a trend to an increase in hepatic recurrence did not reach statistical significance. Due to the relatively small number of patients in the individual subgroups, no firm conclusion can be drawn from this. A further limitation is selection bias. The decision to use the PM was at the discretion of individual surgeons. The PM may have been applied for more challenging cases due to the complexity, higher blood loss or more damaged liver parenchyma. This may also help explain the higher hepatic recurrence rate (which did not achieve statistical significance) in patients with R1 and PM resections.

Due to the differences and lack of details on the reasons PM were applied in certain cases, it is difficult to make a definitive conclusions regarding a non-statistically difference in diseasefree survival favoring PM group in R0 patients (19 vs. 12 months,P= 0.069). Given that it is not statistically significant, it may merely represent a natural variance in data. Equally, it is possible,although by no means probable that PM may confer an advantage for more complicated resections by allowing a clearer (blood free)operative field, which may then influence survival.

In conclusion, the application of PM was not associated with a significant difference in disease-free and overall survival in patients who underwent hepatic resection for CRLM. Although the study showed a higher rate of hepatic recurrence following an R1 resection when PM was applied, this was not statistically significant. The PM remains a safe technique.

Acknowledgments

None.

CRediT authorship contribution statement

Li Lian Kuan : Investigation, Methodology, Validation, Visualization, Writing - original draft, Writing - review & editing. Christopher P Neal : Data curtion, Formal analysis, Investigation, Methodology, Resources, Software, Writing - original draft. Vaux Robertson : Data curtion, Formal analysis, Investigation, Methodology, Resources, Software, Writing - original draft. Michael Jones : Data curtion, Formal analysis, Investigation, Methodology, Resources,Software, Writing - original draft. Ashley R Dennison : Conceptualization, Formal analysis, Supervision, Validation, Visualization,Writing - review & editing. Giuseppe Garcea : Conceptualization,Formal analysis, Investigation, Methodology, Project administration,Resources, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing.

Funding

None.

Ethical approval

This study was approved by the Ethics Committee of Leicester General Hospital.

Competing interest

No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.