Abstract
Introduction
Portal pedicle clamping (PPC) may impact micro-metastases’ growth. This study examined the association between PPC and survival after a hepatectomy for colorectal liver metastases (CRLM).
Methods
A matched cohort study was conducted on hepatectomies for CRLM at a single institution (2003–2012). Cohorts were selected based on PPC use, with 1:1 matching for age, time period and the Clinical Risk Score. Outcomes were overall and recurrence-free survival (OS and RFS). Cox regression was performed to assess the association between PPC and survival.
Results
Of 481 hepatectomies, 26.9% used PPC. One hundred and ten pairs of patients were matched in the cohorts. There was no significant difference in OS [hazard ratio (HR) 1.18; 95% confidence interval (CI): 0.76–1.83], with a 5-year OS of 57.8% (95%CI: 52.4–63.2%) with PPC versus 62.3% (95%CI: 57.1–67.5%) without. Five-year RFS did not differ (HR 0.98; 95%CI: 0.71–1.35) with 29.7% (95%CI: 24.9–34.5%) with PPC versus 28.0% (95%CI: 23.2–32.8%) without. When adjusting for extent of resection, transfusion, operative time and surgeon, there was no difference in OS (HR 0.91; 95%CI: 0.52–1.60) or RFS (HR: 0.86; 95%CI: 0.57–1.30).
Conclusions
PPC was not associated with a significant difference in OS or RFS in a hepatectomy for CRLM. PPC remains a safe technique during hepatectomy.
Introduction
Hepatectomy has become the standard of care for curative intent treatment of colorectal liver metastases (CRLM). With broader patient selection and effective multimodal approaches, overall survival (OS) ranges from 30% to 60% at 5 years.1 However, recurrence remains common and occurs in up to 60% of patients following initial hepatectomy.2
Due to advances in surgical techniques and peri-operative care, the morbidity profile of hepatectomy has improved significantly, with current peri-operative mortality now nearing 1% in high-volume centres.3,4 However, blood loss and need for a transfusion remain a significant concern that can impact both immediate and long-term outcomes.5–7 Numerous intra-operative strategies have been developed to limit blood loss.8–10 Of these, portal pedicle clamping (PPC), first described by Hogarth Pringle for liver trauma,11 is one of the only strategies proven effective to reduce intra-operative blood loss in randomized controlled trials.12,13
Despite evidence of the efficacy and safety of PPC with regards to post-operative morbidity and liver failure, the uptake of PPC is highly variable. While 30% of Canadian hepato-pancreatico-biliary surgeons use PPC, 40% do so in the United Kingdom, 50% in Japan and 70% in Continental Europe.14–17 Concerns remain regarding the long-term oncological effects of PPC due to ischemia–reperfusion injury to the liver remnant.18,19 Current evidence defining the precise effect of PPC on oncological outcomes in a CRLM resection is restricted to studies with small sample sizes from individual hospitals and cohorts spanning the introduction of modern patient selection and multi-modal therapy.20–23
The purpose of this study was to ascertain the effect of PPC on long-term oncological outcomes in a contemporary cohort of patients undergoing hepatectomy for CRLM.
Patients and methods
A retrospective matched cohort study of a prospectively maintained database was conducted. This study was approved by the Sunnybrook Health Sciences Centre Research Ethics Board.
Patient selection
Patients were identified from a prospectively maintained institutional database at a tertiary care hepato-pancreatico-biliary surgery academic centre (Sunnybrook Health Sciences Centre – Odette Cancer Centre). Adult patients (≥18 years of age) undergoing an elective liver resection for CRLM from 2003 to 2012 were included.
Patients who underwent PPC were identified and then matched 1:1 with patients who did not undergo PPC. Matching criteria were age (≤40 years old, 5-year increments, and ≥70 years old), time period of operation (2003–2007, 2008–2012) and clinical risk score (one-point increments from 0 to 5). The clinical risk score was computed with one point assigned for each of: node-positive primary malignancy, disease-free interval < 12 months, more than one hepatic metastasis, largest hepatic metastasis measuring more than 5 cm and pre-hepatectomy carcinoembryonic antigen >200 ng/ml.24 The time period cut-off of 2008 was selected to correspond with the routine introduction of peri-operative systemic treatment of CRLM at our institution.25 Patients were categorized according to the matching criteria and a random number generator used to match corresponding pairs within the same categories. All PPC patients with a matched control available were included in the analysis to optimize the sample size. Post-hoc power calculation was conducted.
Outcomes and data collection
The primary outcome was overall survival (OS), defined as date of hepatectomy to date of death. The secondary outcome was recurrence-free survival (RFS), defined as date of hepatectomy to date of recurrence.
The database was queried for data on baseline demographics, pre-operative systemic treatment, pre-operative biochemical parameters, intra-operative factors and post-operative clinical course, including recurrence. Major liver resection was defined as a resection of 3 or more liver segments. Major morbidity included grade 3 to 5 Clavien–Dindo complications.26 Recurrence was defined as intra- or extra-hepatic biopsy-proven recurrent adenocarcinoma or lesion deemed suspicious on cross-sectional imaging. Death data were obtained from the Ontario Cancer Registry (OCR), a provincial administrative database of Ontario residents diagnosed with cancer since 1964, receiving hospital discharge records, pathology reports, death certificates and reports from regional cancer centres in the province of Ontario.27
Technical considerations
Liver resections were performed aiming for low central venous pressure. Intermittent PPC was used at the discretion of the operating surgeon (no longer than 15 min clamped with 5–10 min unclamped). Hepatic pre-conditioning is not routinely used. After hepatectomy for CRLM, patients are initially followed every 3–6 months clinically and radiologically with cross-sectional imaging of the chest, abdomen and pelvis, for 5 years.
Statistical analysis
Descriptive analysis was performed to compare the characteristics of patients who underwent PPC with those who did not. Categorical variables were reported as absolute number (n) with proportion (%), and continuous variables as the median with interquartile range (IQR). Groups were compared using Pearson's chi-square test, Fisher's exact test and ANOVA, as appropriate.
Survival analysis was performed using the Kaplan–Meier method.28 Dates of death from the OCR as of August 8th, 2014 were used, providing a minimum of 24 months of follow-up data for all patients in the cohort. The end of follow-up for OS analysis was considered as date of death or August 8th, 2014. For RFS, date of first recurrence was used, with end of the last follow-up defined as date of recurrence, date of death or date of the last clinical encounter. A sensitivity analysis was conducted for OS and RFS in patients alive 90 days after a hepatectomy. Differences in OS and RFS were calculated using the log-rank test.28 The association between PPC and survival was assessed with Cox regression analysis. Multi-variable Cox regression was used to adjust for relevant clinico-therapeutic variables identified a priori: operative time (continuous, in hours), receipt of a red blood cell transfusion (categorical), major liver resection defined as ≥3 segments (categorical) and surgeon (categorical). Results of Cox regression were reported as hazard ratios (HR) with 95% confidence interval (95% CI). Statistical significance was set at P < 0.05. All analyses were conducted with SPSS 22.0 (IBM Corp., Amon, NY, USA).
Results
Among 851 hepatectomies performed during the study period, 483 were treated for CRLM. Two of those were excluded due to missing data on PPC use, leaving 481 patients undergoing a liver resection for CRLM. Of those, 129 (26.9%) underwent PPC. Four different surgeons performed the hepatectomies during the study period. Characteristics of the entire cohort, based on the use of PPC, are detailed in Table 1. The proportion of cases for which they used PPC varied (P < 0.0001), with 37.6% (50/133), 17.8% (40/224), 31.2% (29/93) and 31.3% (10/31). The median cumulative PPC time was 20 min (IQR: 15–30 min).
Table 1.
Characteristics of patients undergoing a hepatectomy for colorectal liver metastases, based on portal pedicle clamping (PPC) status, in the entire cohort
| PPC (n = 129) | No PPC (n = 352) | P-value | |
|---|---|---|---|
| Time period 2008–2012 a | 78 (60.5) | 251 (71.3) | 0.023 |
| Age (years old)a | 63 (55–70) | 64 (54.2–72.7) | 0.635 |
| Male Gender | 78 (60.5) | 219 (62.2) | <0.0001 |
| Pre-operative haemoglobin (g/l) | 133.5 (120.2–145) | 135 (123–145) | 0.128 |
| Pre-operative bilirubin (μmol/l) | 7 (5–10) | 8 (6–11) | 0.755 |
| Pre-operative INR | 0.98 (0.94–1.03) | 0.98 (0.94–1.03) | 0.664 |
| Pre-operative albumin (g/l) | 42 (40–45) | 42 (39.5–44) | 0.881 |
| Pre-operative creatinine (μmol/l) | 76 (63.7–85.2) | 74 (61.2–87) | 0.802 |
| Pre-operative platelet count (109/l) | 212.5 (179–252.7) | 219 (183–268) | 0.151 |
| Clinical risk score a | |||
| 0 | 8 (6.2) | 44 (12.5) | 0.06 |
| 1 | 41 (31.8) | 77 (21.9) | |
| 2 | 38 (29.5) | 122 (34.7) | |
| 3 | 35 (27.1) | 91 (25.9) | |
| 4 | 7 (5.4) | 15 (4.3) | |
| 5 | 0 (0) | 3 (0.9) | |
| Pre-operative chemotherapy | 111 (86.0) | 298 (84.7) | <0.0001 |
| Major liver resectionb | 98 (76.6) | 256 (72.7) | 0.235 |
| Estimated blood loss (l) | 1 (0.5–1.7) | 1 (0.5–1.5) | 0.182 |
| Operative time (hours) | 5.2 (4.1–6.2) | 4.4 (3.4–5.7) | <0.0001 |
| Intra-operative complication | 6 (4.7) | 22 (6.3) | <0.0001 |
| Perioperative RBC transfusion | 34 (26.3) | 98 (27.8) | 0.828 |
| Major morbidity | 18 (13.9) | 60 (17.0) | 0.380 |
| 90-day mortality | 10 (7.7) | 13 (3.7) | <0.0001 |
| Length of stay (days) | 7 (6–9) | 7 (6–10) | 0.128 |
| 30-day re-admission | 2 (1.6) | 16 (4.5) | <0.0001 |
| Resection margin status | |||
| R0 | 116 (89.9) | 318 (90.3) | 0.358 |
| R1 | 6 (4.7) | 15 (4.3) | |
| R2 | 1 (0.8) | 12 (0.6) | |
| Unknownc | 6 (4.7) | 17 (4.8) | |
Values are n (%) or median (inter-quartile range).
Factors used for matching.
Major liver resection: ≥ 3 liver segments resected.
Margin status could not be identified in the pathology report.
INR, International Normalized Ratio; RBC, red blood cell.
One hundred and ten patients undergoing PPC were matched to patients operated on without PPC, for a total of 220 patients included in the matched cohort comparative analysis (Fig. 1). Characteristics of this matched cohort are presented in Table 2. No difference was observed in therapeutic parameters, including the use of pre-operative chemotherapy, the performance of a major liver resection, estimated blood loss, operative time and resection margins. The post-operative course did not differ significantly based on the use of PPC, including post-operative morbidity, mortality, length of stay and the need for a red blood cell transfusion.
Figure 1.
Flow diagram of patient selection
Table 2.
Characteristics of patients undergoing hepatectomy for colorectal liver metastases, based on PPC status, in the matched cohort
| PPC (n = 110) | No PPC (n = 110) | P-value | |
|---|---|---|---|
| Time period 2008–2012 a | 72 (65.5) | 72 (65.5) | 1.00 |
| Age (years old)a | 63.0 (56.0–72.0) | 63.0 (56.0–71.2) | 0.921 |
| Male Gender | 67.0 (60.9) | 75 (68.2) | 0.286 |
| Pre-operative haemoglobin (g/l) | 134.0 (122.0–145.5) | 135.0 (123.0–143.0) | 0.281 |
| Pre-operative bilirubin (μmol/l) | 7.0 (5.0–9.0) | 8.0 (6.0–11.7) | 0.241 |
| Pre-operative INR | 0.98 (0.93–1.02) | 0.98 (0.94–1.03) | 0.721 |
| Pre-operative albumin (g/l) | 42.0 (40.0–44.7) | 42.0 (39.0–45.0) | 0.942 |
| Pre-operative creatinine (μmol/l) | 76.0 (63.0–84.7) | 75.0 (62.0–88.0) | 0.445 |
| Pre-operative platelet count (109/l) | 208.0 (174.5–250.0) | 217.0 (188.0–271.5) | 0.035 |
| Clinical risk scorea | |||
| 0 | 8 (7.3) | 8 (7.3) | 1.00 |
| 1 | 32 (29.1) | 32 (29.1) | |
| 2 | 37 (33.6) | 37 (33.6) | |
| 3 | 29 (26.4) | 29 (26.4) | |
| 4 | 4 (2.6) | 4 (2.6) | |
| 5 | 0 (0) | 0 (0) | |
| Pre-operative chemotherapy | 94 (85.5) | 87 (79.1) | 0.217 |
| Major liver resectionb | 69 (63.3) | 67 (60.9) | 0.715 |
| Estimated blood loss (l) | 1.0 (0.5–1.8) | 1.0 (0.5–1.5) | 0.232 |
| Operative time (hours) | 5.1 (4.0–6.1) | 4.5 (3.4–5.9) | 0.057 |
| Intra-operative complication | 5 (4.5) | 9 (8.2) | 0.322 |
| Peri-operative RBC transfusion | 31 (28.2) | 26 (23.9) | 0.465 |
| Major morbidity | 16 (14.5) | 20 (18.2) | 0.429 |
| 90-day mortality | 8 (7.3) | 7 (6.4) | 0.404 |
| Length of stay (days) | 7.0 (6.0–9.0) | 8.0 (6.0–11.0) | 0.100 |
| 30-day re-admission | 1 (0.9) | 5 (4.5) | 0.098 |
| Resection margin status | |||
| R0 | 98 (89.1) | 102 (92.7) | 0.366 |
| R1 | 6 (5.5) | 1 (1.8) | |
| R2 | 1 (0.9) | 0 (0) | |
| Unknownc | 5 (4.5) | 6 (5.5) | |
Values are n (%) or median (inter-quartile range).
Factors used for matching.
Major liver resection: ≥3 liver segments resected.
Margin status could not be identified in the pathology report.
RBC, red blood cells.
With a sample size of 220 patients with a 1:1 distribution and 66 events, this analysis had 80% power to detect an HR of 1.18 (alpha = 0.05). Overall survival analysis is presented in Fig. 2. After a median follow-up of 33 (IQR: 20.1–54.8) months from the date of death, OS did not differ based on the use of PPC (HR 1.18; 95%CI: 0.76–1.83). Actuarial 3-year and 5-year OS in the PPC and no PPC groups were, respectively, 65.8% (95% CI: 61.0–70.6%) versus 73.6% (95% CI: 69.3–77.9%), and 57.8% (95% CI: 52.4–63.2%) versus 62.3% (95% CI: 57.1–67.5%). After adjustment for operative time, red blood cell transfusion, major liver resection and surgeon, the HR associated with PPC remained non-significant at 0.91 (95% CI: 0.52–1.6). Excluding patients who died in the first 90 days did not alter the results, with an unadjusted HR of 1.08 (95% CI: 0.63–1.84) and an adjusted HR of 0.66 (95% CI: 0.34–1.31).
Figure 2.
Overall survival after a hepatectomy for colorectal liver metastases, based on portal pedicle clamping (PPC) status, for the entire cohort (a) and for 90-day survivors (b)
For assessment of recurrence, the median follow-up was 23.1 (IQR: 7.7–43.3) months. The median time to recurrence did not differ: 9.9 (5.7–18.7) months with PPC and 7.9 (3.9–5.7) months without PPC (P = 0.175). The results of the RFS analyses are detailed in Fig. 3. No significant difference was observed in RFS (HR: 0.98; 95% CI: 0.71–1.35). Actuarial RFS was 35.6% (95% CI: 30.9–40.3%) with PPC versus 38.7% (95% CI: 33.9–43.5%) without PPC at 3 years, and 28.0% (95% CI: 23.2–32.8%) with PPC versus 29.7% (95% CI: 24.9–34.5%) without PPC at 5 years. Adjustment for operative time, red blood cell transfusions, a major liver resection and surgeon revealed an HR of 0.86 (95% CI: 0.57–1.30). Results did not change when restricting the analysis to 90-day survivors with an unadjusted HR of 0.96 (95% CI: 0.68–1.37) and an adjusted HR of 0.82 (95% CI: 0.52–1.28).
Figure 3.
Recurrence-free survival after a hepatectomy for colorectal liver metastases (CRLM), based on portal pedicle clamping (PPC) status, for the entire cohort (a) and for 90-day survivors (b)
Discussion
This study compared the long-term outcomes of PPC for a CRLM resection in a cohort matched on age, clinical risk score and time period. In this purposefully balanced cohort for known baseline prognostic factors, neither OS nor RFS differed based on the use of PPC.
PPC has been studied extensively and shown to be safe with respect to morbidity and mortality. In addition, the use of PPC is associated with decreased blood loss and the need for blood transfusions.12,13,29 Despite these benefits, adoption of PPC varies widely around the world, perhaps because of concerns regarding its oncologic impact in overall and recurrence-free survival.14–17 The present study was designed with a view to address this issue.
In the peri-operative period, there was no difference between the PPC and a non-PPC group with respect to peri-operative morbidity and mortality, in concordance with other series.12,13,29 Although PPC has been shown to reduce the amount of blood loss and need for blood transfusions, there was no difference between our two cohorts. However, there is substantial selection bias as PPC was used at the discretion of the surgeon in this non-randomized series. In addition, patients were matched on prognostic factors pertaining to long-term outcomes and not to the risk of transfusion, such that effect of PPC on the need for a transfusion cannot be accurately assessed in this study.
The original impetus for concern regarding ischemia/perfusion created with PPC in inducing rapid growth of liver metastases arose from observations in animal studies.30–32 For instance, one murine model of liver metastases reported a five- to six-fold increase in hepatic metastasis growth in liver lobes subjected to PPC.32 Several hypotheses have been suggested to understand the complex local hepatic response to the ischemia/reperfusion process and explain these observations, both acute (early liver tissue damage) and chronic effects (tissue necrosis).32 Acute hepatocellular injury from inflammatory cytokines, neutrophil infiltration, hepatocytes edema, an imbalance in pro-constriction and pro-dilation vasoactive substances and the coagulation system have all been incriminated.33–37 By creating a fertile ground for tumour growth, such phenomena could theoretically translate into higher recurrence rates in humans undergoing a hepatectomy for CRLM. The results presented herein do not support this hypothesis.
Previous works have assessed the impact of PPC on oncologic survival outcomes, but were hampered by small sample sizes, imbalance in the use of PPC and/or time periods bridging the introduction of modern selection criteria and peri-operative systemic therapy for CRLM resection.18–23,38 A case-matched analysis conducted on 60 pairs of patients described a trend in improved 5-year OS and significantly improved 5-year RFS with PPC, but was limited by the exclusion of patients with higher-risk disease.20,24 Other results are consistent with the lack of a difference in OS and RFS observed in the present study.18,22,23 Most of those studies spanned across long time periods, ranging from 1991 to 2008, during which patient selection, surgical technique and peri-operative medical therapies have significantly changed with an impact on outcomes,1,25 thus limiting their generalizability to contemporary management. While some analyses were based on large cohorts of up to 900 hepatectomies, they were biased by the high frequency of PPC utilization ranging from 65% to 88% of cases and a lack of matching techniques to account for the inherent selection bias.21,22 Finally, one study focused on the long-term follow-up of patients entered in a randomized, controlled trial aimed at assessing the impact of PPC on short-term post-hepatectomy morbidity, from 2002 to 2004.18 It did not observe a difference in OS or RFS, but it included only 80 patients and was not powered to detect survival differences.
The present study is the largest matched cohort analysis of oncological outcomes for PPC during hepatectomy for CRLM. Confounders introduced by patient selection were taken into consideration by matching on number and size of liver lesions included in the CRS and multivariable regression accounting for surrogates of technical challenge (operative time, red blood cell transfusion and major resection).24 Such detailed analysis strengthens the findings. This study focused on OS and all site RFS. The data available in the institutional database did not allow for reliable assessment of the patterns of recurrence with specific assessment of liver RFS, which could theoretically be more affected by PPC. However, beyond the pattern of recurrence, OS was not affected by PPC, and remains one of the most clinically relevant appraisal tools of a cancer patient's ultimate outcome. Finally, the exact impact of prolonged cumulative PPC time could not be assessed due to small numbers within the PPC group and the overall short median cumulative PPC time (20 min). The original PPC murine models focused on longer continuous PPC time than that used with the intermittent clamping technique.32 Thus far, only one group has suggested that the impact of PPC on OS and RFS may be more apparent only in prolonged PPC, based on a sub-group of 50 patients and without accounting for selection bias.19 This observation has been refuted by others.18,21–23
This study is subject to the inherent weaknesses of its retrospective design, including selection bias, information bias and unknown confounders. First, the decision to proceed with PPC was dependent on the surgeon. Second, PPC might have been used for more difficult cases due to more complex disease, higher blood loss or more damaged liver parenchyma. As previously mentioned, prognostic factors were controlled for by matching cohorts, and known confounders pertaining to a technical challenge and surgical risk were adjusted for by multivariable regression analysis. Additionally, the current findings are limited to the intermittent PPC technique and cannot be extrapolated to the continuous one. Finally, details of recurrence patterns were not reliably captured as patients often had their care returned to the referring centre.
Conclusion
In this study, PPC was not associated with OS and all-site RFS in patients undergoing a hepatectomy for CRLM in patients matched for age, time period of operation and clinical risk score. PPC does not negatively affect oncological outcomes and remains a safe strategy in hepatectomy for CRLM.
Funding sources
None.
Conflict of interest
None declared.
References
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