Ann Surg Oncol DOI 10.1245/s10434-015-4478-3

ORIGINAL ARTICLE – HEPATOBILIARY TUMORS

The Influence of Aging on Hepatic Regeneration and Early Outcome after Portal Vein Occlusion: A Case–Control Study Nadia Russolillo1, Francesca Ratti2, Luca Vigano`3, Serena Langella1, Federica Cipriani2, Luca Aldrighetti2, and Alessandro Ferrero1 Department of General and Oncological Surgery, Ospedale Mauriziano ‘‘Umberto I’’, Turin, Italy; 2Liver Unit, Department of Hepatobiliary Surgery, San Raffaele Hospital, Milan, Italy; 3Liver Surgery Unit, Department of Surgery, Humanitas Clinical and Research Center, Rozzano, Milan, Italy 1

ABSTRACT Background. Portal vein occlusion (PVO) is used to increase inadequate future liver remnant volume (FLRV). Impaired liver regeneration has been reported in aged animals. This study was designed to evaluate the impact of patient age on hepatic regeneration. Methods. Sixty patients aged C70 years were matched 1:1 with 60 patients aged \70 years. Matching criteria were sex, diabetes, cirrhosis, pre-PVO chemotherapy and bevacizumab administration, and jaundice. Results. The median ages in the older and younger groups were 76 (range 70–83) years and 59 (range 20–69) years, respectively (p \ 0.001). Median FLRV following PVO (33.1 ± 6.8 vs. 31.9 ± 6.0 %) and volumetric increase (0.52 ± 0.35 vs. 0.49 ± 0.34) were similar in the two groups. Of the older and younger patients, 10 % and 1.7 %, respectively, did not undergo liver surgery after PVO (p = 0.051). Mortality (5.5 vs. 6.7 %) and major morbidity (25.9.8 vs. 22 %) rates were similar. Liver failure rate was higher in older patients (35.1 vs. 16.9 %, p \ 0.026), mainly due to Grade A liver failure (20.3 vs. 8.4 %, p \ 0.001). Multivariate analysis showed that age C 70 years [odds ratio (OR) 3.03; 95 % confidence interval (CI) 1.18–7.78; p = 0.020] and biliary cancer diagnosis (OR 4.69; 95 % CI 1.81–12.09; p = 0.001) were independent risk factors for postoperative liver failure. Conclusions. Liver regeneration after PVO is not impaired by age. Nevertheless, liver resection in elderly patients is performed less often after PVO and carries a higher risk of liver failure.

Future liver remnant volume (FLRV) is a predictor of postoperative hepatic dysfunction.1 Portal vein occlusion (PVO) by embolization (PVE) or ligation (PVL) is routinely used to increase inadequate FLRV in patients scheduled for major hepatectomy or trisectionectomy.2 Several factors have been associated with reduced hepatic regeneration, including male sex, diabetes, liver cirrhosis, biliary obstruction, and administration of chemotherapy.3–9 Controlling these factors whenever possible is essential to maximize liver hypertrophy. The impact of age on liver regeneration capacity is largely unknown. Several experimental studies showed that liver proliferative capacity was reduced and liver regeneration impaired in aged animals following partial resection or chemically induced injury.10–12 Few clinical studies have assessed the effects of aging on hepatic regeneration, with liver regeneration capacity in elderly patients evaluated mostly from experience in living-donor liver transplantation (LDLT).13–21 Evidence has indicated that the function and regeneration of allografts were poorer from aged than from younger LDLT donors.17–19,21 In addition, older donor age was associated with increased risks to both graft and patient survival.15 In these studies, Although the age cutoff point in these studies was almost 50 years, the median age at diagnosis of a malignant hepatobiliary (HPB) tumor is usually C70 years, indicating that more than 50 % of patients with liver or bile duct carcinoma are older than age 70 years.22 This case-matched study was designed to evaluate the impact of age C70 years on hepatic regeneration after PVO.

Ó Society of Surgical Oncology 2015

METHODS

First Received: 16 December 2014 N. Russolillo e-mail: [email protected]

The study population included all consecutive patients scheduled for PVO before major hepatectomy or

N. Russolillo et al.

trisectionectomy between January 2000 and June 2013 at two Italian HPB centers (Mauriziano Umberto I Hospital, Turin, and San Raffaele Hospital, Milan). Patients with missing preand/or post-PVO computed tomography (CT) scans and those scheduled for associated liver partition with portal vein ligation for staged hepatectomy were excluded. Age itself was not an absolute contraindication to surgery. PVO was planned when the estimated FLRV, based on the scheduled hepatectomy, was \25 % in patients with a normal liver, \30 % in those with chronic liver disease or intensive preoperative chemotherapy, and \40 % in patients with a cirrhotic liver.23,24 Liver resection was performed 4 weeks later if sufficient hypertrophy had occurred. PVO consisted of either percutaneous embolization of the right portal vein, with or without embolization of segment 4 portal branches, or surgical ligation of the portal branch.25,26 In jaundiced patients, PVE was performed after percutaneous decompression of the biliary tract on the side of the liver to be left in. Chemotherapy before liver resection was administered to initially unresectable patients (conversion therapy) and to selected resectable patients (neoadjuvant chemotherapy). A short treatment was scheduled (4–6 cycles) and surgery was planned at response. PVO was performed at least 30 days after interruption of chemotherapy and 40 days after administration of the last dose of bevacizumab. FLRV was expressed as the ratio of FLRV to nontumorous total liver volume measured directly by CT scan.27 Liver regeneration was assessed by the increase in volume [(FLRV%post - FLRV%pre)/ FLRV %pre]. Major hepatectomy was defined as the resection of C3 Couinaud’s segments.28 Hepatic insufficiency was defined as an increased international normalized ratio and concomitant hyperbilirubinemia C5 days postoperatively.29 Operative mortality was defined as death within 90 days after surgery or before discharge from the hospital. Morbidity included all postoperative complications and was classified as described.30 Complications of grade III or higher were defined as major morbidity. Hepatic insufficiency grades B and C were considered major complications. Patients were identified from two prospectively collected hepatobiliary databases and retrospectively analyzed. All statistical analyses were performed with Stat Soft version 7.0 (Verona, Italy). Categorical variables were compared using the Chi square test or Fisher’s exact test, as appropriate. Continuous variables were compared using unpaired t tests or Mann–Whitney U tests, as appropriate. Statistical significance was defined as p \ 0.05. The study was approved by the local ethical committee. RESULTS Sixty patients aged C70 years were matched one-to-one with 60 of the 199 patients aged \70 years scheduled for PVO during the study period. Matching criteria were the most relevant factors affecting liver regeneration capacity:

sex (male vs. female); diagnosis of diabetes mellitus (yes vs. no); liver cirrhosis (yes vs. no); administration of chemotherapy before PVO (yes vs. no); administration of bevacizumab before PVO (yes vs. no); and biliary obstruction (yes vs. no).3–9 Patient Characteristics Table 1 summarizes the characteristics of the patients. Each group consisted of 40 males (66.7 %) and 20 females (33.3 %). In each group, 16 (27 %) patients were diagnosed with diabetes, 10 (16.7 %) with liver cirrhosis, and 17 (28.3 %) with jaundice before PVO. The median ages of the older and younger groups were 76 (range 70–83) years and 59 (range 20–69) years, respectively (p \ 0.001). Indication for resection in the older and younger groups included metastatic disease [29 (48.3 %) vs. 30 (50 %), p = 0.855], biliary cancer [20 (33.3 %) vs. 19 (31.6 %), p = 0.843], and primary liver cancer [11 (18.3 %) vs. 11 (18.3 %), p = 1.00]. Sixteen (26.7 %) patients in each group received pre-PVO chemotherapy (matching criteria); the mean number of cycles before PVO were 6.0 ± 3.0 in the older group and 6.5 ± 2.8 in the younger group (p = 0.399). Chemotherapy regimens in the older group included oxaliplatin in six (37.5 %) patients, irinotecan in six (37.5 %), and other drugs in four (25 %). Of the younger patients, nine (56.2 %) received oxaliplatin, six (37.5 %) received irinotecan, and one (1.7 %) received 5-fluorouracil. Twelve patients who received chemotherapy in each group also received bevacizumab. PVO Details and Volumetric Data (Table 2) Mean FLRV before PVO was similar in the older and younger groups (21.8 ± 5.6 vs. 22.1 ± 5.5 %, p = 0.388), as was the percentage of patients with pre-PVO FLRV \20 % (30 vs. 38.3 %, p = 0.335). Liver hypertrophy was induced by PVE in 50 (83.3 %) older and 52 younger (86.7 %) patients (p = 0.609), with the remaining patients in both groups undergoing PVL during the first stage of two-stage hepatectomy. Post-PVE complications were more frequent in older patients (13.4 vs. 3.4 %, p = 0.047), with two older patients experiencing partial migration of embolized material in segment 4 after right PVE. Nevertheless, CT scan-volumetry showed adequate liver hypertrophy in both. One younger patient required a second embolization, because the Sg7 portal branch was still patent after the first procedure. Adequate liver hypertrophy was achieved in all but one of the older patients. Mean post-PVO FLRV (33.1 ± 6.8 vs. 31.9 ± 6.0 %, p = 0.554; Fig. 1) and volumetric increase (0.52 ± 0.35 vs. 0.49 ± 0.34, p = 0.582; Fig. 2) were similar in the older and younger groups.

Liver Regeneration in Aged Patients TABLE 1 Patient characteristics Group old n = 60 n (%)

Group young n = 60 n (%)

p

\0.001

Patient characteristics Age (years)

73 (70–83)

59 (20–69)

Male sex

40 (66.7)

40 (66.7)

1 (matched)

BMI

23.9 ± 4.5

25.6 ± 4.7

0.835

Diabetes

16 (26.7)

16 (26.7)

1 (matched)

Biliary obstruction

17 (28.3)

17 (28.3)

1 (matched)

Liver cirrhosis Chemotherapy before PVO

10 (16.7) 16 (26.7)

10 (16.7) 16 (26.7)

1 (matched) 1 (matched)

Bevacizumab before PVO

12 (20)

12 (20)

1 (matched)

Chemotherapy after PVO

1 (1.7)

3 (5)

0.309

Liver resection after PVO

54 (90)

59 (98.4)

0.051

Trisectionectomy

24 (44.4)

32 (54.2)

0.298

Two-stage hepatectomy

13 (24)

16 (27.1)

0.711

13 (100)

15 (93.7)

0.829

12 (22.3)

14 (23.7)

0.849

Operative data

Completed Associated resections

Continuous variables are reported as median value (range) Significant p value are given in bold BMI body mass index, PVO portal vein occlusion, ns not significant

TABLE 2 PVO detailed and volumetric data Group old n = 60

Group young n = 60

p

Median FLR (%) before PVO

21.8 ± 5.6 %

22.1 ± 5.5 %

0.388

FLR \20 %

19 (33.3)

23 (38.3)

0.335

PVE/PVL

50/10

52/8

0.609

PVE dx/PVE dx ? S4

47/3

47/5

0.379

Complication post PVE (%)

8 (13.4)

2 (3.4)

0.047

4 (8)

1 (2.1)

1.000

Fever Liver disfunction

2 (4)

1 (2.1)

1.000

Migration of embolized material

2 (4)

0

1.000

Interval between PVO-CT scan volumetry (days)

35.5 ± 6.8

34.0 ± 6.8

0.375

Median FLR (%) post PVO

33.1 ± 6.8

31.9 ± 6.0

0.554

Volumetric Increase

0.52 ± 0.35

0.49 ± 0.34

0.582

Continuous variables are reported as median value (range) Significant p value are given in bold FLR future remnant liver volume, Ctx chemotherapy, PVO portal vein occlusion, PVE portal vein occlusion, PVL portal vein ligation, ns not significant

Operative and Postoperative Results (Table 3) A higher percentage of older than of younger patients did not undergo liver surgery after PVO (10 vs. 1.7 %, p = 0.051). The causes of dropout were inadequate volumetric increase in one older patient and progressive disease in the other five patients in the older group and the one patient in the younger group. The proportion of patients undergoing trisectionectomy was similar in the

older and younger groups (44.4 vs. 54.2 %, p = 0.298). In addition to liver resections, 12 patients in the older group (22.3 %) and 14 in the younger group (23.7 %) underwent additional procedures (p = 0.849). Two-stage hepatectomy was planned in 13 (24 %) older patients and 16 (27.1 %) younger patients (p = 0.711), but one older patient could not undergo the second stage because of disease progression. Mean blood loss during parenchymal transection was similar in the older and younger groups (355 ± 2814 ml

N. Russolillo et al. 60

Median

25%-75%

Min-Max

55

FLRV post PVO (%)

50 45

p= 0.554 40 35 30 25 20 15

Age≥70

Age

The Influence of Aging on Hepatic Regeneration and Early Outcome after Portal Vein Occlusion: A Case-Control Study.

Portal vein occlusion (PVO) is used to increase inadequate future liver remnant volume (FLRV). Impaired liver regeneration has been reported in aged a...
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