Abstract
Background:
Pre-operative chemotherapy for colorectal liver metastasis (CRLM) is thought to be the cause of hepatotoxicity of non-tumoural parenchyma. Studies on hepatotoxicity are contradictory. We investigated the impact of a single-line pre-operative chemotherapy on non-tumoural liver analysed by an expert hepatico-pancreatico-biliary pathologist, and the consequences on surgical outcomes.
Patients and methods:
Patients operated for CRLM, after a pure first-line pre-operative chemotherapy, were retrospectively included. Two comparative histopathological analyses were performed for vascular toxicity and steatohepatitis.
Results:
Between 2003 and 2015, 147 patients were included. Chemotherapy was based on oxaliplatin (40.1%), irinotecan (55.8%), or both (4.1%). The expert pathologist described 38.8% of vascular lesions including dilation, nodular regeneration, and peliosis. In multivariate analysis, vascular lesions correlated to male sex (P = .01), pre-operative platelets <150 g/L (P = .04), and aspartate aminotransferase to platelet ratio index (APRI) score >0.36 (P = .02). Steatohepatitis was observed in 15 patients (10.2%), more frequently after irinotecan (14.8% vs 3.4%, P = .01; odds ratio [OR] = 7.3; 95% confidence interval [CI] = [1.5-34.7]), and for patients with body mass index (BMI) >25 kg/m2 (P = .004; OR = 10.0; 95% CI = [2.1-47.5]). A total of 29 patients (19.7%) developed major complications with 2 risk factors: portal vein obstruction (PVO) and septic surgery. Reproducibility assessment of steatohepatitis and dilated lesions by 2 pathologists showed moderate agreement (Kappa score 0.53 and 0.54, respectively).
Conclusions:
There is a probable association between non-alcoholic steatohepatitis (NASH) and irinotecan. Oxaliplatin seems to lead to higher vascular lesions. Except in the presence of pre-existent comorbidities, liver toxicities should not restrain the use of pre-operative chemotherapy prior to parenchymal-sparing surgery.
Keywords: colorectal cancer, hepatic metastasis, neoadjuvant chemotherapy, vascular toxicity, steatohepatitis, hepatotoxicity
Introduction
Liver surgery with complete resection of colorectal cancer liver metastases (CRLMs) improves long-term survival.1,2 In primarily resectable metastases, pre-operative chemotherapy allows selecting patients with better prognosis, maximising remnant liver, and reducing local recurrence compared to surgery alone.3 In unresectable metastases, chemotherapy reduces the disease enabling complete resectioning in 12.5% to 30% of cases.4 Pre-operative chemotherapy based on oxaliplatin and/or irinotecan may be involved in histological damage, vascular lesions, or steatohepatitis, despite conflicting results from studies.5,6 This hepatotoxicity could reduce liver function of the future remnant liver (FRL) and increase post-operative complications.6,7
Nevertheless, risk factors for steatosis and non-alcoholic steatohepatitis (NASH) exist even without any chemotherapy, for example, in obesity and diabetes. Moreover, histological assessment of sinusoidal obstruction syndrome (SOS) and steatohepatitis has limitations and requires an experienced pathologist.8,9 In general, reports in literature on the impact of chemotherapy on non-tumoural liver and on post-operative morbidity and mortality are heterogeneous with contradictory conclusions.10–13
The aim of this study was to investigate the factors associated with hepatotoxicity on non-tumoural liver due to pre-operative chemotherapy. We analysed only patients who received exclusively one line of chemotherapy, operated by parenchymal-sparing surgery with 2 comparative histopathological analyses (a routine pathological examination and an expert assessment).
Methods
Patients
Patients operated on for CRLM, between January 2003 and May 2015, were retrospectively identified from our prospectively maintained database (Base FOI, Medlog™). Patients treated with only one line of pre-operative chemotherapy were included. Patients with chronic liver disease, treated with adjuvant chemotherapy with FOLFOX (and not 5-fluouracil alone) or 2 different lines of pre-operative chemotherapy, were excluded. Details on patient selection and surgical methods are given in Supplementary Material.
Histological analysis
Histological analysis of non-tumoural hepatic parenchyma was performed using archived material (prepared from formalin-fixed, paraffin-embedded tissue). Morphological analysis was based on haematoxylin and eosin (H&E), Masson trichrome, and reticulin stains. The pathologists were unaware of the clinical data. Patients were excluded when the slides were too close to the metastases or presented surgical hepatitis. First analysis was made by our pathologist followed by a second analysis by an expert from the university hospital. Results from the second analyses were used as reference. In the second part, we analysed inter-observer interpretation and the impact on main results. Histological features of parenchymal, stromal, and vascular changes were evaluated and graded according to Rubbia-Brandt et al5,9 Classification. The standard scores for the evaluation of steatosis and steatohepatitis or NASH were adopted, as defined by Kleiner et al.14
Statistical methods
The statistical analyses were performed using SAS software Version 9.3 (Cary, NC). Categorical variables were described using their size and percentages; quantitative variables using their median and range (min-max). In univariate analysis, predictive factors of post-operative complications and of histological lesions were obtained using the chi-square or Fisher exact tests for comparing categorical variables; the Wilcoxon non-parametric test was used to compare continuous variables. A P <.05 was considered to be statistically significant. In multivariate analysis for post-operative complications, significant factors were introduced in a stepwise logistic regression. Weighted kappa scores were used to measure the degree of inter-observer agreement between the 2 pathologists.
Results
Patient characteristics, pre-operative treatment, and surgery
The chemotherapy regimens used every 2 weeks before surgery were as follows:
LV5FU2: folinic acid 400 mg/m2 in 2 hours + 5FU 400 mg/m2 in 10 minutes + 5FU 2400 mg/m2 in 46 hours
with or without bevacizumab 5 mg/kg
FOLFIRI: irinotecan 180 mg/m2 in 90 minutes + LV5FU2
with or without bevacizumab 5 mg/kg
with or without panitumumab 6 mg/kg
with or without cetuximab 500 mg/m2 every 2 weeks
FOLFOX 4: oxaliplatin 85 mg/m2 in 2 hours + LV5FU2
with or without bevacizumab 5 mg/kg
with or without panitumumab 6 mg/kg
with or without cetuximab 500 mg/m2
FOLFIRINOX: irinotecan 180 mg/m2 + oxaliplatin 85 mg/m2 + LV5FU2
with or without bevacizumab 5 mg/kg
with or without panitumumab 6 mg/kg
with or without cetuximab 500 mg/m2
A total of 319 patients were operated on for CRLM. In total, 153 patients did not meet chemotherapy inclusion criteria. Three had hepatitis virus infection and 76 patients were excluded on histological criteria. Finally, 147 patients matched the inclusion criteria whose clinico-pathological characteristics are given in Table 1. A major liver resection was performed in 58 (39.5%) patients. Intra-operative radiofrequency ablation and resection were performed in 67 patients (45.6% cases). Portal vein obstruction (PVO) by embolisation (by the radiologist) or by ligature plus alcoholisation (during the surgery) was used in 18 patients in whom post-hepatectomy liver failure was considered to be a threat due to a small FRL. Two-stage hepatectomies were planned in 11 cases, but the disease progressed in 4 patients prior to the second intervention, which was cancelled. An extra-hepatic procedure was performed in 66 (44.9%) patients and was potentially contaminating in 38 (25.9%) patients.
Table 1.
Clinico-pathological characteristics of patients (N = 147).
| Variable | No. of patients | % | Number (min-max) |
|---|---|---|---|
| Median age, y | 64 (34-88) | ||
| Sex | |||
| Female | 61 | 41.5 | |
| Male | 86 | 58.5 | |
| Body mass index, kg/m 2 | |||
| Median | 25 (17-47) | ||
| <25 | 72 | 49 | |
| ⩾25 | 75 | 51 | |
| ⩾30 | 19 | 12.9 | |
| Diabetes mellitus | |||
| Present | 13 | 8.8 | |
| Absent | 134 | 91.2 | |
| Arterial hypertension | |||
| Present | 65 | 44.2 | |
| Absent | 82 | 55.8 | |
| Dyslipidaemia | |||
| Present | 37 | 25.2 | |
| Absent | 110 | 74.8 | |
| Primary tumour site | |||
| Colon | 120 | 81.6 | |
| Rectum | 27 | 18.4 | |
| Hepatic metastasis | |||
| Synchronous | 111 | 75.5 | |
| Metachronous | 36 | 24.5 | |
| Initially resectable | 79 | 53.7 | |
| Initially unresectable | 68 | 46.3 | |
Vascular lesions: predictive and risk factors
Histological lesions in non-tumoural liver were described in 87 (59.2%) patients (Table 2). Vascular lesions, including dilation, nodular regeneration, and peliosis, were considered significant based on our definition in 57 patients (38.8%). Steatohepatitis or NASH was observed in 15 (10.2%) patients and steatosis >5% in 82 (55.8%) patients.
Table 2.
Incidence of liver injuries in non-tumoural parenchyma.
| Liver injury | No. of patients | % |
|---|---|---|
| Sinusoidal dilation | ||
| No | 77 | 52.8 |
| Yes | 69 | 47.2 |
| Grade 1 | 44 | 30.1 |
| Grade 2 | 17 | 11.6 |
| Grade 3 | 8 | 5.5 |
| Nodular regeneration | ||
| No | 85 | 58.2 |
| Yes | 61 | 41.8 |
| Grade 1 | 38 | 26.0 |
| Grade 2 | 13 | 8.9 |
| Grade 3 | 10 | 6.8 |
| Vascular toxicity | ||
| No | 90 | 61.2 |
| Yes | 57 | 38.8 |
| Grade <5 | 126 | 86.3 |
| Grade ⩾5 | 20 | 13.7 |
| Chemotherapy-associated steatohepatitis | ||
| No | 132 | 89.8 |
| Yes | 15 | 10.2 |
| Steatosis | ||
| <5% | 65 | 44.2 |
| Of 5 at 33% | 58 | 39.5 |
| Of 33 at 66% | 19 | 12.9 |
| >66% | 5 | 3.4 |
| Lobular inflammation | ||
| Absent | 103 | 70.1 |
| ⩽2/foci | 40 | 27.2 |
| 2-4/foci | 4 | 2.7 |
| ⩾4/foci | 0 | 0 |
| Ballooning | ||
| 0 | 112 | 76.2 |
| 1 | 31 | 21.1 |
| 2 | 4 | 2.7 |
Predictive factors for vascular lesions, including congestion and/or nodular lesions, are described in Table 3. In univariate analysis, male sex, pre-operative platelets <150 g/L, oxaliplatin, and aspartate aminotransferase to platelet ratio index (APRI) score >0.36 were correlated with the development of vascular lesions. Patients receiving oxaliplatin developed more vascular lesions than without (50% vs 30.5%; P = .016). Five patients had abnormally high level of bilirubin before chemotherapy and 10 patients before surgery had more vascular toxicity. In multivariate analysis, sex (P = .01), platelets (P = .04), and APRI remained correlated with vascular lesions. An APRI score >0.36 correlated to a higher incidence of vascular lesions: 57.1% vs 28.3% of patients with an APRI score ⩽0.36 (P = .02, 134 patients, odds ratio [OR] = 2.9; 95% confidence interval [CI] = [1.2-7.3]). Oxaliplatin and bilirubin levels were not retained as independent risk factors of vascular lesions.
Table 3.
Predictive factors of vascular histologic lesions in non-tumoural parenchyma.
| Characteristics | Vascular toxicity (N = 57) |
Total | P, univariate analysis | P, multivariate analysis | OR [95% CI] | |||
|---|---|---|---|---|---|---|---|---|
| Absent |
Present |
|||||||
| No. | % | No. | % | |||||
| Sex | ||||||||
| Male | 44 | 51.2 | 42 | 48.8 | 86 | |||
| Female | 45 | 75.0 | 15 | 25.0 | 60 | .004 | .01 | 0.3 [0.1-0.8] |
| Chemotherapy with oxaliplatin | ||||||||
| Yes | 32 | 50.0 | 32 | 50.0 | 64 | |||
| No | 57 | 69.5 | 25 | 30.5 | 82 | .016 | NR | |
| Chemotherapy with irinotecan | ||||||||
| Yes | 59 | 67.0 | 29 | 33.0 | 88 | |||
| No | 30 | 51.7 | 28 | 48.3 | 58 | .06 | ||
| Number of cycles | ||||||||
| ⩽8 | 46 | 61.3 | 29 | 38.7 | 75 | |||
| >8 | 43 | 60.6 | 28 | 39.4 | 71 | .82 | ||
| Targeted therapy | ||||||||
| Bevacizumab | 44 | 69.8 | 19 | 30.2 | 63 | |||
| None or other | 45 | 54.2 | 38 | 45.8 | 83 | .55 | ||
| APRI score | ||||||||
| ⩽0.36 | 65 | 71.4 | 26 | 28.6 | 91 | |||
| >0.36 | 18 | 42.8 | 24 | 57.1 | 42 | .002 | .02 | 2.9 [1.2-7.3] |
| Bilirubin before chemotherapy | ||||||||
| ⩽1N | 71 | 69.6 | 31 | 30.4 | 102 | |||
| >1N | 1 | 20 | 4 | 80 | 5 | .038 | NR | |
| Pre-operative bilirubin | ||||||||
| ⩽1N | 65 | 69.1 | 29 | 30.9 | 94 | |||
| >1N | 4 | 40 | 6 | 60 | 10 | .022 | NR | |
| Pre-operative platelets | ||||||||
| ⩾150 g/L | 86 | 66.2 | 44 | 33.8 | 130 | |||
| <150 g/L | 2 | 15.4 | 11 | 84.6 | 13 | .0003 | .04 | 10.1 [1.2-89.5] |
Abbreviations: APRI, aspartate aminotransferase to platelet ratio index; CI, confidence interval; NR, not retained at multivariate analysis; OR, odds ratio.
Out of the 2 different types of vascular lesions, congestion lesions and non-nodular lesions tended to associate with pre-operative oxaliplatin (P = .064). For patients receiving oxaliplatin, bevacizumab had a protective effect on the development of vascular lesions (P = .04). Oxaliplatin seems to have a high impact on the development of severe vascular lesions with severe toxicity in 26.6% of patients against only 3.7% that did not (P < .0001). Number of chemotherapies and the time between the end of chemotherapy and liver surgery had no effect on the incidence of vascular lesions.
Steatohepatitis: predictive and risk factors
In univariate analysis, irinotecan, body mass index (BMI) >25 kg/m2, dyslipidaemia, pre-operative gamma-glutamyltransferase level >N, and bilirubin >N were related to more steatohepatitis lesions (Table 4). Multivariate analysis on 15 patients with NASH, irinotecan, and BMI >25kg/m2 remained statistically associated with NASH. In patients treated with or without irinotecan, NASH was observed in 14.8% and 3.4%, respectively (P = .01; OR = 7.3; 95% CI = [1.5-34.7]); a BMI >25 kg/m2 was linked to more NASH (P = .004; OR = 10.0; 95% CI = [2.1-47.5]). Neither the duration of chemotherapy nor the delay between surgery and the end of the chemotherapy had an impact on incidence of NASH.
Table 4.
Predictive factors of NASH in non-tumoural parenchyma.
| Characteristics | NASH (N = 15) |
Total | P, univariate analysis | P, multivariate analysis | OR [95% CI] | |||
|---|---|---|---|---|---|---|---|---|
| Absent |
Present |
|||||||
| No. | % | No. | % | |||||
| Dyslipidaemia | ||||||||
| Yes | 29 | 78.4 | 8 | 21.6 | 37 | |||
| No | 101 | 93.5 | 7 | 6.5 | 108 | .02 | NR | |
| Diabetes | ||||||||
| Yes | 10 | 76.9 | 3 | 23.1 | 13 | |||
| No | 121 | 91.0 | 12 | 9.0 | 133 | .13 | ||
| Arterial hypertension | ||||||||
| Yes | 56 | 86.2 | 9 | 13.8 | 65 | |||
| No | 75 | 92.6 | 6 | 7.4 | 81 | .20 | ||
| Body mass index | ||||||||
| ⩽25 kg/m² | 70 | 97.2 | 2 | 2.8 | 72 | |||
| >25 kg/m² | 62 | 82.7 | 13 | 17.3 | 75 | .004 | .004 | 10.0 [2.1-47.5] |
| Chemotherapy with irinotecan | ||||||||
| Yes | 75 | 85.2 | 13 | 14.8 | 88 | |||
| No | 57 | 96.6 | 2 | 3.4 | 59 | .03 | .01 | 7.3 [1.5-34.7] |
| Chemotherapy with oxaliplatin | ||||||||
| Yes | 63 | 96.9 | 2 | 3.1 | 65 | |||
| No | 69 | 84.1 | 13 | 15.9 | 82 | .01 | ||
| Number of cycles | ||||||||
| ⩽8 | 67 | 88.2 | 9 | 11.8 | 76 | |||
| >8 | 65 | 91.5 | 6 | 8.5 | 71 | .50 | ||
| Pre-operative GGT | ||||||||
| ⩽1N | 67 | 93.1 | 5 | 6.9 | 72 | |||
| >1N | 49 | 86 | 8 | 14 | 57 | .045 | NR | |
| Pre-operative bilirubin | ||||||||
| ⩽1N | 89 | 93.7 | 6 | 6.3 | 95 | |||
| >1N | 8 | 80 | 2 | 20 | 10 | .033 | NR | |
Abbreviations: CI, confidence interval; GGT, gamma-glutamyltransferase; NASH, non-alcoholic steatohepatitis; NR, not retained at multivariate analysis; OR, odds ratio.
Post-operative outcomes and risk factors
In total, 78 patients (53.1%) developed post-operative complications, including 29 (19.7%) major complications and 31 (21.1%) liver-related complications. Supplementary Table S1 details the post-operative complications. Ninety-day mortality rate was 0.7% (one septic shock on a post-operative bilioma). Two patients had a splenomegaly, possibly related to chemotherapy.
Risk factors of poorer post-operative outcomes were analysed and are described in Table 5. Patients’ characteristics, pre-operative type of treatment, or presence of histological lesions were not correlated to more complications or more liver-related complications.
Table 5.
Impact of clinico-pathological characteristics, pre-operative treatments, surgery protocols, and histological injuries on post-operative outcomes, in univariate analysis.
| Characteristics | Post-operative complications |
Total | P, univariate analysis | P, multivariate analysis | OR [95% CI] | |||
|---|---|---|---|---|---|---|---|---|
| No or grade <3 |
Grade ⩾3 |
|||||||
| No. | % | No. | % | |||||
| Total | 118 | 80.3 | 29 | 19.7 | 147 | |||
| Chemotherapy | ||||||||
| Oxaliplatin | 47 | 79.7 | 12 | 20.3 | 59 | |||
| Irinotecan | 66 | 80.5 | 16 | 19.5 | 82 | |||
| Both | 5 | 83.3 | 1 | 16.7 | 6 | .90 | ||
| Number of cycles | ||||||||
| ⩽8 | 69 | 84.1 | 13 | 15.9 | 82 | |||
| >8 | 66 | 78.6 | 18 | 21.4 | 84 | .36 | ||
| Targeted therapy | ||||||||
| None | 45 | 81.8 | 10 | 18.2 | 55 | |||
| Bevacizumab | 49 | 77.8 | 14 | 22.2 | 63 | |||
| Other | 24 | 82.8 | 5 | 17.2 | 29 | .72 | ||
| Liver surgery extension | ||||||||
| Minor | 71 | 79.8 | 18 | 20.2 | 89 | |||
| Major | 47 | 81.0 | 11 | 19.0 | 58 | .85 | ||
| Pre-operative PVO | ||||||||
| Yes | 10 | 55.6 | 8 | 44.4 | 129 | |||
| No | 108 | 83.7 | 21 | 16.3 | 18 | .01 | .004 | 5.4 [1.7-16.6] |
| Two-stage hepatectomy | ||||||||
| Yes | 6 | 54.5 | 5 | 45.5 | 11 | |||
| No | 112 | 82.4 | 24 | 17.6 | 136 | .04 | ||
| Extra-hepatic surgery | ||||||||
| Yes | 46 | 69.7 | 20 | 30.3 | 66 | |||
| No | 72 | 88.9 | 9 | 11.1 | 81 | .004 | NR | |
| Septic surgery | ||||||||
| Yes | 23 | 60.5 | 15 | 39.5 | 38 | |||
| No | 95 | 87.2 | 14 | 12.4 | 109 | .001 | <.001 | 5.2 [2.1-13.1] |
| Vascular lesion | ||||||||
| Absence | 74 | 83.2 | 15 | 16.8 | 89 | |||
| Presence | 43 | 75.4 | 14 | 24.6 | 57 | .25 | ||
| Absent or grade <5 | 101 | 80.2 | 25 | 19.8 | 126 | |||
| Grade ⩾5 | 16 | 80.0 | 4 | 20.0 | 20 | .99 | ||
| NASH | ||||||||
| Absence | 105 | 79.6 | 27 | 20.4 | 132 | |||
| Presence | 13 | 86.7 | 2 | 13.3 | 15 | .74 | ||
| APRI score | ||||||||
| ⩽0.36 | 73 | 79.3 | 19 | 20.7 | ||||
| >0.36 | 36 | 85.7 | 6 | 14.3 | .38 | |||
Abbreviations: APRI, aspartate aminotransferase to platelet ratio index; CI, confidence interval; NASH, non-alcoholic associated steatohepatitis; NR, not retained in multivariate analysis; OR, odds ratio; PVO: portal vein obstruction.
In univariate analysis, 4 surgical characteristics were related to poorer outcomes: two-stage hepatic surgeries, PVO, extra-hepatic surgery, and a potentially contaminating procedure. In multivariate analysis, only PVO and septic surgery were associated with more grade ⩾3 post-operative complications. Two-stage hepatectomies (including PVOs) and extra-hepatic surgery (P = .14) were not used in the multivariate models. Major complications were associated with a higher blood requirement and a longer time at hospital.
APRI score >0.36 did not correlate with poorer post-operative outcomes. Among the 25 patients with grade ⩾3 complications and a calculated APRI score, only 6 (24%) had a score >0.36. Time between the end of chemotherapy and surgery was not significantly different for the occurrence of post-operative complications when two-stage surgeries were excluded. Among the biological parameters, post-operative aspartate aminotransferase (AST) levels below 1.5N during the 2 days after surgery were predictive for complications: 57.1% of patients (4 of 7) with AST ⩽1.5N had severe complications vs 18% (25 of 139 patients) with AST >2N (P = .03).
Comparison of the 2 histological analyses
We compared the histologic descriptions by an expert hepatico-pancreatico-biliary pathologist to those of our general pathologist. Reproducibility was assessed using the Kappa score. For NASH, analyses’ agreement was 90.5%, with a Kappa score of 0.53 (moderate agreement). Indeed, 9 patients were considered ‘with NASH lesions’ and ‘without NASH’ by our pathologist and the expert, respectively, and 5 patients had a NASH according to the expert and no lesion according to our pathologist, suggesting that among the 15 NASH diagnosed, only one was concordant. For steatosis measurement, comparing no steatosis or steatosis <5% vs >5% steatosis, the Kappa score was very high, 0.82 (95% CI = [0.69-0.95]). On the contrary, for inflammation and balloon lesion assessments, scoring only agreed at levels expected by chance: r = 0.05 and r = –0.04.
Regarding vascular lesions, only dilated lesions were analysed by both pathologists. The Kappa score showed a moderate agreement (0.54). A total of 166 patients could be analysed using the routine pathologist assessment results, whereas only 147 patients by the expert analysis; the expert eliminated 19 patients (2 missed strains, 17 lack of non-tumoural liver with presence of surgical hepatitis). According to statistical analyses using our general pathologist results, oxaliplatin and irinotecan were not correlated with higher rates of SOS/sinusoidal dilation and NASH, respectively. These results differ with previously described results from the expert, demonstrating an impact of irinotecan on the incidence of steatohepatitis. Body mass index was correlated with NASH in both analyses. The 2 histological analyses were in agreement to conclude that the presence of histopathological lesions did not worsen post-operative outcomes. Septic surgery was associated with more grade ⩾3 post-operative complications whatever the histological analysis, but PVO was significantly associated with more complications only with the expert results.
Discussion
The aim of this study was to investigate the predisposing factors for hepatotoxicity due to pure first-line pre-operative chemotherapy on the non-tumoural liver, analysed by an expert hepatico-pancreatico-biliary pathologist, and the consequences on surgical outcomes in a series of parenchymal-sparing surgeries. Nevertheless, the main limitation of our work is the lack of a histological assessment of cancer-free liver before chemotherapy.
After 10 years and many studies, results are still heterogeneous, including patients with different and incomparable chemotherapies, without essential and exhaustive histological analysis.10,12–17 Our study is interesting as the patients received only one line of chemotherapy, giving us pertinent and homogeneous results on the impact of chemotherapy on liver. The study by Rubbia-Brandt et al9 did not show any impact of sex, contrary to our results.
Probable association between oxaliplatin and vascular lesions
Rubbia-Brandt et al5,9 reported high rates (51%) of vascular lesions after pre-operative chemotherapy with oxaliplatin or irinotecan. In our study, oxaliplatin tended to have an impact on the development of vascular lesions. However, other chemotherapies may also have an effect: 30% of patients receiving no oxaliplatin had vascular lesions. We observed lower incidence of vascular lesions and less severe lesions, probably because of the limited number of pre-operative chemotherapies (only 8 cycles).7 In our results, bevacizumab seems to have a protective effect against vascular toxicity when associated with oxaliplatin, in agreement with previous studies.9,18 Biological predictive factors of vascular lesions were statistically significant: low pre-operative platelets and an APRI score >0.36. These factors could be useful to select patients with a high risk of vascular toxicity, which should lead to a prudent parenchymal saving surgery.14,18
Supplementary Table S2 lists some of the publications on pre-operative chemotherapy and its impact on non-tumoural liver, with some conflicting results.12,15 These differences could be a result of difficulty in diagnosing and assessing vascular lesions, confirming the importance of an expert analysis.9,11 These results are consistent with intra- and inter-observer variations published by Pilgrim et al10 where in the Spearman correlation coefficients were weak, 0.52 and 0.53, respectively.
Probable association between irinotecan and NASH
Irinotecan was implicated by Vauthey et al6 in the incidence of chemotherapy-associated steatohepatitis (CASH) (20.2%). There have been reports on the association between other chemotherapies (5-FU alone, FOLFIRI, or FOLFOX) and CASH.10,19 On the contrary, confounding factors such as BMI or diabetes could influence the development of CASH.8,12,20 The absence of histological differences between pre-existent NASH and CASH may impede understanding the role of irinotecan in the development of steatohepatitis. Of note, NASH is observed in around 5.7% to 17% of the general population.21
Our results are relevant to these studies as NASH and CASH are similar histological lesions with the same pathogenic mechanism. Hence, the risk factors such as BMI, dyslipidaemia, diabetes, and chemotherapy influenced the development of steatohepatitis (Supplementary Table S2). Furthermore, one limitation of our study is the absence of a control group without pre-operative chemotherapy, which we deemed not necessary as this was not the aim of our study. Nevertheless, our population represents the general population, matching on the sex and age proportions, different parameters of metabolic syndrome: diabetes, arterial hypertension, dyslipidaemia, and BMI. Therefore, we can conclude that patients receiving oxaliplatin and not irinotecan have a similar incidence of NASH compared to the general population.22 Our results are consistent with Pilgrim et al,10 with the Spearman correlation coefficients good for steatosis, but not favourable for ballooning and inflammation lesions, as a consequence of steatohepatitis. Moreover, lesions have a heterogeneous distribution inside the liver.23
Correlation between type of neoadjuvant chemotherapy, surgical methods, histological lesions, and post-operative outcomes
Most of the reports on outcomes impacted by chemotherapies have used non-parenchymal-sparing strategies, where in the quantity of normal parenchyma retrieved at each procedure was possibly more than in our series. Nakano et al7 found that SOS was correlated with an increased risk of post-operative complications but only if a major resection was practised. Sinusoidal lesions have been associated with an increased blood requirement and higher post-operative liver failure,20,24 but no poorer outcomes in other studies.6,12,25–28 The extent of liver resection, and hence the FRL, is a determinant factor for complications.11,29,30 The negative impact of chemotherapy on post-operative outcomes has been suggested by Nordlinger et al,3 but lacked non-tumoural liver analysis. Hepatotoxicity could reduce liver function of the FRL which should not measure below 30% to 40% of liver.6,7 The type and number of chemotherapies may influence these complications with 6 or 8 cycles showing an augmentation of risks.31,32
Potential septic surgery is also known to cause higher post-operative complications.13,28,30 As often in extensive surgeries, PVO was correlated with higher post-operative complications. In the literature, PVO seems to improve liver volume and function,33 but is associated with more post-operative complications (blood loss) and may stimulate the growth of the remaining metastases.34 Rubbia-Brandt et al9 found no impact of PVO on histological non-tumoural liver lesions. On the whole, PVO has to be restricted to the patients having a clear risk of post-hepatectomy liver failure and only if one-stage treatment is not possible.35
Our data have not shown an association between liver injury and outcome. Nevertheless, this retrospective study of 147 patients over a 12-year period is underpowered to demonstrate any association between histological lesions (vascular lesions or steatohepatitis) and post-operative outcomes. Indeed, Vauthey et al6 have demonstrated a 10-fold higher post-operative mortality in the presence of steatohepatitis in a cohort of over 400 patients. Other larger studies on the same topic also conflict with our conclusions.6,10,20,21
Conclusions
The results of our study are in agreement with the literature and show a probable association between the development of NASH and irinotecan and suggest that pre-existent comorbidities may influence this outcome. We also conclude that oxaliplatin seems to lead to higher vascular lesions. Except in specific cases, liver toxicities cannot be used as an argument to proscribe or restrain the use of pre-operative chemotherapy as it is particularly useful in parenchymal-sparing surgery. Nevertheless, our data are underpowered to demonstrate an association between liver injury and outcome.
Supplemental Material
Supplemental material, Supplementary_Material for Hepatotoxicities Induced by Neoadjuvant Chemotherapy in Colorectal Cancer Liver Metastases: Distinguishing the True From the False by Marie Desjardin, Benjamin Bonhomme, Brigitte Le Bail, Serge Evrard, Véronique Brouste, Gregoire Desolneux, Marianne Fonck, Yves Bécouarn and Dominique Béchade in Clinical Medicine Insights: Oncology
Acknowledgments
The authors would like to thank Dr Ravi Nookala of Institut Bergonié for the medical writing service.
Footnotes
Funding:The author(s) received no financial support for the research, authorship, and/or publication of this article.
Declaration of conflicting interests:The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Author Contributions: DB contributed to study concepts. MD contributed to study design. BB contributed to data acquisition. VB contributed to statistical analysis. MD, BLB, GD, MF, YB, SE, and DB contributed to data analysis and interpretation. MD, MF, SE, and DB contributed to manuscript preparation, editing, and review.
Ethics and Consent: The institutional review board waived the need for ethics and consent due to retrospective nature of the study.
Supplemental material: Supplemental material for this article is available online.
ORCID iD: Dominique Béchade 
https://orcid.org/0000-0001-9504-920X
References
- 1. Abdalla EK, Adam R, Bilchik AJ, Jaeck D, Vauthey JN, Mahvi D. Improving resectability of hepatic colorectal metastases: expert consensus statement. Ann Surg Oncol. 2006;13:1271–1280. [DOI] [PubMed] [Google Scholar]
- 2. Rees M, Tekkis PP, Welsh FK, OʼRourke T, John TG. Evaluation of long-term survival after hepatic resection for metastatic colorectal cancer: a multifactorial model of 929 patients. Ann Surg. 2008;247:125–135. [DOI] [PubMed] [Google Scholar]
- 3. Nordlinger B, Sorbye H, Grimelius B, et al. Perioperative FOLFOX4 chemotherapy and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC 40983): long-term results of a randomised, controlled, phase 3 trial. Lancet Oncol. 2013;14:1208–1215. [DOI] [PubMed] [Google Scholar]
- 4. Adam R, Delvart V, Pascal G, et al. Rescue surgery for unresectable colorectal liver metastases downstaged by chemotherapy: a model to predict long-term survival. Ann Surg. 2004;240:644–657. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Rubbia-Brandt L, Audard V, Sartoretti P, et al. Severe hepatic sinusoidal obstruction associated with oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer. Ann Oncol. 2004;15:460–466. [DOI] [PubMed] [Google Scholar]
- 6. Vauthey JN, Pawlik TM, Ribero D, et al. Chemotherapy regimen predicts steatohepatitis and an increase in 90-day mortality after surgery for hepatic colorectal metastases. J Clin Oncol. 2006;24:2065–2072. [DOI] [PubMed] [Google Scholar]
- 7. Nakano H, Oussoultzoglou E, Rosso E, et al. Sinusoidal injury increases morbidity after major hepatectomy in patients with colorectal liver metastases receiving pre-operative chemotherapy. Ann Surg. 2008;247:118–124. [DOI] [PubMed] [Google Scholar]
- 8. Bower M, Wunderlich C, Brown R, Scoqqins CR, McMasters KM, Martin RC. Obesity rather than neoadjuvant chemotherapy predicts steatohepatitis in patients with colorectal metastasis. Am J Surg. 2013;205:685–690. [DOI] [PubMed] [Google Scholar]
- 9. Rubbia-Brandt L, Lauwers GY, Wang H, et al. Sinusoidal obstruction syndrome and nodular regenerative hyperplasia are frequent oxaliplatin-associated liver lesions and partially prevented by bevacizumab in patients with hepatic colorectal metastasis. Histopathology. 2010;56:430–439. [DOI] [PubMed] [Google Scholar]
- 10. Pilgrim CH, Satgunaseelan L, Pham A, et al. Correlations between histopathological diagnosis of chemotherapy-induced hepatic injury, clinical features, and perioperative morbidity. HPB (Oxford). 2012;14:333–340. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11. Ryan P, Nanji S, Pollett A, et al. Chemotherapy-induced liver injury in metastatic colorectal cancer: semiquantitative histologic analysis of 334 resected liver specimens shows that vascular injury but not steatohepatitis is associated with preoperative chemotherapy. Am J Surg Pathol. 2010;34:784–791. [DOI] [PubMed] [Google Scholar]
- 12. Wolf PS, Park JO, Bao F, et al. Preoperative chemotherapy and the risk of hepatotoxicity and morbidity after liver resection for metastatic colorectal cancer: a single institution experience. J Am Coll Surg. 2013;216:41–49. [DOI] [PubMed] [Google Scholar]
- 13. Desolneux G, Vara J, Razafindratsira T, et al. Patterns of complications following intraoperative radiofrequency ablation for liver metastases. HPB (Oxford). 2014;16:1002–1008. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14. Kleiner DE, Brunt EM, Van Natta M, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005;41:1313–1321. [DOI] [PubMed] [Google Scholar]
- 15. Mehta NN, Ravikumar R, Coldham CA, et al. Effect of preoperative chemotherapy on liver resection for colorectal liver metastases. Eur J Surg Oncol. 2008;34:782–786. [DOI] [PubMed] [Google Scholar]
- 16. Martins J, Alexandrino H, Oliveira R, et al. Sinusoidal dilation increases the risk of complications in hepatectomy for CRCLM – protective effect of bevacizumab and diabetes mellitus, serum gamma-glutamyltranspeptidase as predictive factor. Eur J Surg Oncol. 2016;42:713–721. [DOI] [PubMed] [Google Scholar]
- 17. Viganò L, Rubbia-Brandt L, De Rosa G, et al. Nodular regenerative hyperplasia in patients undergoing liver resection for colorectal metastases after chemotherapy: risk factors, preoperative assessment and clinical impact. Ann Surg Oncol. 2015;22:4149–4157. [DOI] [PubMed] [Google Scholar]
- 18. Hubert C, Sempoux C, Humblet Y, et al. Sinusoidal obstruction syndrome (SOS) related to chemotherapy for colorectal liver metastases: factors predictive of severe SOS lesions and protective effect of bevacizumab. HPB (Oxford). 2013;15:858–864. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19. Fernandez FG, Ritter J, Goodwin JW, Linehan DC, Hawkins WG, Strasberg SM. Effect of steatohepatitis associated with irinotecan or oxaliplatin pretreatment on resectability of hepatic colorectal metastases. J Am Coll Surg. 2005;200:845–853. [DOI] [PubMed] [Google Scholar]
- 20. Pathak S, Tang JM, Terlizzo M, Poston GJ, Malik HZ. Hepatic steatosis, body mass index and long term outcome in patients undergoing hepatectomy for colorectal liver metastases. Eur J Surg Oncol. 2010;36:52–57. [DOI] [PubMed] [Google Scholar]
- 21. Gomez D, Malik HZ, Bonney GK, et al. Steatosis predicts post-operative morbidity following hepatic resection for colorectal metastasis. Br J Surg. 2007;94:1395–1402. [DOI] [PubMed] [Google Scholar]
- 22. McCullough AJ. Pathophysiology of nonalcoholic steatohepatitis. J Clin Gastroenterol. 2006;40:S17–S29. [DOI] [PubMed] [Google Scholar]
- 23. Goldstein NS, Hastah F, Galan MV, Gordon SC. Fibrosis heterogeneity in nonalcoholic steatohepatitis and hepatitis C virus needle core biopsy specimens. Am J Clin Pathol. 2005;123:382–387. [DOI] [PubMed] [Google Scholar]
- 24. Wicherts DA, de Haas RJ, Sebagh M, et al. Regenerative nodular hyperplasia of the liver related to chemotherapy: impact on outcome of liver surgery for colorectal metastases. Ann Surg Oncol. 2011;18:659–669. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25. Morris-Stiff G, White AD, Gomez D, et al. Nodular regenerative hyperplasia (NRH) complicating oxaliplatin chemotherapy in patients undergoing resection of colorectal liver metastases. Eur J Surg Oncol. 2014;40:1016–1020. [DOI] [PubMed] [Google Scholar]
- 26. Mullen JT, Davenport DL, Hutter MM, et al. Impact of body mass index on perioperative outcomes in patients undergoing major intra-abdominal cancer surgery. Ann Surg Oncol. 2008;15:2164–2172. [DOI] [PubMed] [Google Scholar]
- 27. Parkin E, O’Reilly DA, Adam R, et al. Equivalent survival in patients with and without steatosis undergoing resection for colorectal liver metastases following pre-operative chemotherapy. Eur J Surg Oncol. 2014;40:1436–1444. [DOI] [PubMed] [Google Scholar]
- 28. Belghiti J, Hiramatsu K, Benoist S, Massault P, Sauvanet A, Farges O. Seven hundred forty-seven hepatectomies in the 1990s: an update to evaluate the actual risk of liver resection. J Am Coll Surg. 2000;191:38–46. [DOI] [PubMed] [Google Scholar]
- 29. Soubrane O, Brouquet A, Zalinski S, et al. Predicting high grade lesions of sinusoidal obstruction syndrome related to oxaliplatin-based chemotherapy for colorectal liver metastases: correlation with post-hepatectomy outcome. Ann Surg. 2010;251:454–460. [DOI] [PubMed] [Google Scholar]
- 30. Hiwatashi K, Ueno S, Sakoda M, et al. The evaluation of liver function and surgical influence by ICGR15 after chemotherapy for colorectal liver metastases. J Cancer. 2016;7:595–599. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31. Karoui M, Penna C, Amin-Hashem M, et al. Influence of pre-operative chemotherapy on the risk of major hepatectomy for colorectal liver metastases. Ann Surg. 2006;243:1–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32. Ribeiro HS, Costa WL, Jr, Diniz AL, et al. Extended preoperative chemotherapy, extent of liver resection and blood transfusion are predictive factors of liver failure following resection of colorectal liver metastasis. Eur J Surg Oncol. 2013;39:380–385. [DOI] [PubMed] [Google Scholar]
- 33. Meier RP, Toso C, Terraz S, et al. Improved liver function after portal vein embolization and an elective right hepatectomy. HPB (Oxford). 2015;17:1009–1018. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34. Elias D, De Baere T, Roche A, Ducreux M, Leclere J, Lasser P. During liver regeneration following right portal embolization the growth rate of liver metastases is more rapid than that of the liver parenchyma. Br J Surg. 1999;86:784–788. [DOI] [PubMed] [Google Scholar]
- 35. Evrard S, Mathoulin-Pelissier S. Controversies between surgical and percutaneous radiofrequency ablation. Eur J Surg Oncol. 2006;32:3–5. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplemental material, Supplementary_Material for Hepatotoxicities Induced by Neoadjuvant Chemotherapy in Colorectal Cancer Liver Metastases: Distinguishing the True From the False by Marie Desjardin, Benjamin Bonhomme, Brigitte Le Bail, Serge Evrard, Véronique Brouste, Gregoire Desolneux, Marianne Fonck, Yves Bécouarn and Dominique Béchade in Clinical Medicine Insights: Oncology