The impact of body mass index on short-term and long-term surgical outcomes of laparoscopic hepatectomy in liver carcinoma patients, a retrospective study

To investigate the inuence of body mass index (BMI) on the short-term and long-term outcomes including disease free survival (DFS) and overall survival (OS) rate in patients with liver carcinoma who underwent laparoscopic hepatectomy (LH) as primary treatment. Methods Data were collected from 137 patients with liver carcinoma who underwent attempted LH between August 2003 and April 2014. Patients were classied into three groups depending on their BMI according to the WHO’s denition of obesity for Asia-Pacic region: underweight (BMI < 18.5 kg/ m 2 , Group1), normal (18.5 ≤ BMI < 23 kg/m 2, Group2), overweight (BMI ≥ 23 kg/m 2, Group3) respectively. Short-term and long-term outcomes including overall survival (OS) and disease free survival (DFS) were compared across the BMI categories. the overall and disease free survival rate in patient with liver carcinoma underwent laparoscopic hepatectomy.

Liver carcinoma is one of the most maligancy cancers in the worldwide and has a particularly high incidence rate in Asian countries. Liver resection is the major way in the treatment of liver cancer and the potential advantage of laparoscopy has been identi ed such as less surgically invasive, fewer complications, and shorter intraoperative hospital stay (1.2). However, the prognosis still remains very poor (3.4). Factors such as age, tumor size and tumor number, pathologic TNM stage, vascular invasion et al have been identi ed to in uence the prognosis for liver cancer patients (5)(6)(7). And now several researchers have found overweight status would increase 17% risk of HCC and obese status would even increase 90% risk of HCC compared with normal weight individuals (8,9) However, the relationship between weight and prognosis of laparoscopic hepatectomy for liver carcinoma remains unclear.
Body mass index (BMI; kg/m 2 ) is a convenient and simple surrogate measure of body fat distribution in clinical setting. And the BMI values used to detect overweight and obese status recommended by the World Health Organization (> 25 kg/m 2 ) were higher than those suggested by Asian population-based studies (22-25 kg/m2) (10)(11). The Working Group on Obesity in China has identi ed that BMI of 23 is the most sensitive and speci c indicator for overweight status of Chinese people (12). Therefore, it is useful to evaluate the association between the prognosis of liver carcinoma and overweight de ned by this BMI value.
The prognosis of liver cancer remains unsatisfactory. Survival rates at 6, 12, 24 months after initial diagnosis have been reported to be 44.1%, 21.7%, and 14.2%, respectively (13). Many studies focused on the Child Pugh score, a-fetoprotein (AFP) concentration to determine the prognosis of liver cancer (14,15).
But the data concerned in uence of underweight and overweight status on this disease has yet to be unde ned. The purpose of this study was to assess the effects of weight using BMI on relevant perioperative complications and the overall and disease free survival rate in patient with liver carcinoma who underwent laparoscopic hepatectomy.

Patients and Diagnosis
Patient selection. A retrospective cohort study that spanned an 11-year period from August 2003 to April 2014 was performed. 137 patients who underwent laparoscopic hepatectomy for liver carcinoma at our institution were identi ed. Institutional Review Board approval for this review was obtained from the Sir Run Run Shaw hospital of Zhejiang University.
According to the WHO's de nition of obesity for the Asia-Paci c region, patients were divided into three groups by BMI: underweight < 18.5 kg/m 2 (Group 1), normal weight 18.5-23 kg/m 2 (Group 2), overweight>23 kg/m 2 (Group 3) (16). BMI was calculated according to a standardized de nition as weight in kilograms divided by height in meters squared and BMI was recorded the day before the surgery.
The diagnosis of liver carcinoma was established using imaging (enhanced computed tomography(CT) or magnetic resonance imaging (MRI)) and pathology reports. And the repeated hepatic resection was excluded from the study.
All patients were followed up until February 2019 and the median follow-up duration was 27 months (range, 2 months).

Surgical Technique
Laparoscopic liver resection was performed as previously described (17). Regional occlusion of liver left/right in ow and out ow instead of total hepatic vascular occlusion was used to minimize liver ischemia reperfusion injury [16]. In the early years of the study (2003)(2004)(2005)(2006), parenchymal transection of the liver was achieved with LPMOD (Peng's multifunction operative dissector, SY-IIIB, Hangzhou ShuYou Medical Equipment Co., Ltd, China) technique. Since 2007, the ultrasonic aspirator (CUSA; Valleylab, Boulder, Colo) has been used for most cases. If there were unclear tumor margin, uncontrolled bleeding, embolism, severe adhesion or other complications, laparoscopic procedure would be changed to open hepatectomy.

Follow-up and Analysis
After being discharged from the hospital, all patients had been followed up monthly within the rst year. The follow-up included physical examinations, computed tomographic scan or magnetic resonance imaging scan, and alpha-feto-protein (AFP) et al. If no recurrence were detected, we would extend the follow-up to a quarterly cadence. Recurrence was de ned as new typical features of mass on imaging, or a rising AFP level. Biopsy was performed when necessary.
Survival was de ned as the interval from the date of diagnosis of liver cancer to the date of death or the last visit before February 2019.

Data analysis
Comparisons between groups were performed with the chi-square test for categorical variables and the Mann-Whitney U-test for continuous variables. DFS and OS were calculated by Kaplan Meier analysis, and the results for subgroups of patients were compared with log-rank test. P<0.05 was regarded as statistically signi cant. All statistical analyses were performed using the SPSS 13.0.

Results
A total of 137 patients was included in the study. Among them, 14 patients (10.22%) were underweight, 65 patients (47.45%) were normal weight and 58 patients (42.34%) were overweight. The basic demographics and tumor characteristics between three groups are summarized in Table 1. The mean body mass index of patients in Group 1, Group 2, and Group 3 were 17.43±1.08, 21.29±1.22, and 25.38±2.68, respectively. Other variables, including age, gender, Child-Pugh score, ASA score, liver cirrhosis, tumor size, tumor number, and the tumor stage have no signi cant difference between the three groups. Table 2 displays the perioperative and postoperative outcomes of the three groups. The conversion rate in the three groups were 16.67%, 27.45%, and 26.09% (P=0.8284), respectively. The mean postoperative hospital length of stay for the three groups was 10.85±4.04 days, 11.57±5.56 days, and 10.88±5.7 days (P=0.7615), respectively. Notably, the overall complication rate in the underweight group was much higher than that in the normal weight and overweight groups (42.85% vs 23.08% vs 17.2%, P=0.048, respectively). And for the postoperative complications, underweight patients developed grade III or higher of the Clavien-Dindo classi cation more easily than the other two groups (P=0.042). In cohort group, bile leak was the most frequent postoperative complication, followed by intraabdominal sepsis, ascites, as well as pneumonia.

Long-term Outcomes
The median follow-up durations in the three groups were 26 months, 30 months and 28 months, respectively. The DFS and OS of the cohort are shown in Table 3. The overall 90-day mortality was 1.46%, and there was no difference between the three groups. The median disease free survival duration of Group 1, 2, and 3 were 28.71 months, 28.08 months, and 33.83 months, respectively. There was no signi cant difference of 1-year DFS between the three groups (p= 0.24). But as for the 3-and 5-year DFS, overweight patients had a longer 3-and 5-years DFS (41.4%, 36.2%) than underweight (21.4%, 14.3%) and normal weight (28.1%, 21.9%) patients (P<0.05). Likewise, the median OS of the three groups were 32.14, 32.43, and 37.09, respectively. And there was no signi cant difference of 1-, 3-, and 5-year OS between the three groups. As to the 5-year OS, overweight patients had a trended of longer 5-year OS (40.8%) than underweight (28.6%) and normal weight (28.1%) patients, but it did not reach statistics signi cance (P>0.05).

Discussion
Laparoscopic hepatectomy has become a feasible option for patients with liver malignancy. As a new technique, researchers have given more attention to short-term and long-term outcomes. Although being overweight and obese does not preclude one to laparoscopy (16), still little is known about the in uence of recipient BMI on the long-term outcomes especially the recurrence rate and the overall survival rate after LH for HCC. In the present study, we observed the patients with elevated BMI accounted for 42.33%. General surgeon will encounter more and more overweight and obese patients with liver cancer in the future. Therefore, it is important to fully understand the effect of elevated BMI on these patients. We carried out this retrospective analysis using our institutional database and we have shown that: (i) being overweight did not increase the conversion rate; (ii) being underweight is associated with an increased number and more severe complications; (iii) being overweight is associated with lower 3-and 5-years tumor recurrence, and being underweight is associated with higher 3-and 5-years tumor recurrence. (iv) being either underweight, normal weight, or overweight had a comparable 1-year and 3-year overall survival rate. But as to 5-years OS, being overweight had a higher chance of survival. It was interesting to detect that being overweight did not have any negative impact on prognosis after LH for liver carcinoma. Actually, a signi cant protective effect of overweight was observed for perioperative complications and tumor recurrence. Meanwhile, being underweight increased risk of perioperative complications and tumor recurrence.
Many studies have demonstrated that the increased BMI would increase the risk of laparoscopic conversion rate and prolong operative time (18,19) and thus the surgeons tended to be reluctant to perform laparoscopic surgery for overweight patients. However, there were no difference of conversion rate and operative time across the three groups in our study, which was consistent with Troisi et al.
analysis (20). This may be because that all laparoscopic procedures were performed by same experienced surgeon team who have nished the learned curve and were capable enough to perform liver tumor using laparoscopic skill, and also there were no patients' BMI more than 40. Meanwhile, not in line with previous studies, which found that overweight patients had a worse outcome than their leaner counterparts (21), our results showed that overweight patients had a lower complication rate (17.2%) compared to the underweight (42.85%) and normal weight patients (23.08%), the decreased BMI values was a risk factor for higher incidence of postoperative complications. We also found severe complications for grade III to IV according to the Clavien classi cation were much higher in underweight group than that in normal weight and overweight group. One cause may be overweight patients are protected by adequate fat storage, better nutrition, and systemic insulin resistance that underweight people do not have (22), Meanwhile the patients with a preoperative lower BMI is more likely to indicate the excessive nutritional consumption and malnutrition resulting from more aggressive tumor (23).
To our knowledge, little research has investigated the association between BMI and prognosis in patients undergoing LH with liver cancer. Yeuh-Shih Chang al reported overweight status had better oncologic outcomes following hepatectomy in HCC patients (24), but the end point of Chang's study was 6-month of survival. The follow-up duration was relatively short, and more data were needed on the overall survival rate as an important therapeutic measure of liver cancer if treatment intensity and life expectancy were judged (25). Our study aimed to verify long-term outcome of liver carcinoma patients who underwent LH, and our data revealed underweight patients had much higher 3-and 5-years cumulative tumor recurrence rate than that in the other two groups. As we know that liver tumors are a consumptive disease, a higher proportion of later stage (stage III) in underweight group in our study was the main cause of a worse outcome. Underweight patients may be malnutrition, possible immune de ciency and then cannot withstand the hepatic resection coupled with other therapies. Also, weight loss or low serum albumin levels of liver disease would be contributed to the high postoperative complications and high 3-and 5years DFS. Our result showed overweight had a better 3-and 5-years DFS and had a tendency of longer 5years overall survival rate. BMI ≥ 23 kg/m 2 is a direct indicator for Asian patients with liver cancer who may bene t from more aggressive anticancer treatment to reduce the tumor recurrence. But as to the overall survival rate, it was comparable between the three groups. Chronic disorders such as cardiovascular disease, hypertension and diabetes, which are closely related to obesity will increase the risk of physical disability and mortality rates in the long run (26). It is reported that nearly 70% of deaths related to high BMI are due to cardiovascular disease and over 60% of those deaths occurs among the obese patients (27). In our study, the high BMI related morality also increased the OS, thus lose the advantage of low tumor recurrence of the overweight group.
Even more, it has been previously reported that postoperative complications had a negative impact on the tumor recurrence and long-term survival rate, especially for severe postoperative complications (28). In our study, we again veri ed that postoperative complication may have an effect on the prognosis of liver cancer patients. We found underweight patients suffered more complications and had a worse DFS. One reason is that the surgical trauma and tissue damage of the complications could result in the immune suppression, and in turn increase the possibility of immune escape and tumor progression (29,30). Secondly, large number of cytotoxic mediators from in ammatory response caused by the infected complications could provide a microenvironment for the growth and invasion of tumor cells, and further promote the development of tumor recurrence (31). At the same time, minimally invasive laparoscopic surgery could avoid the complications such as poor wound healing and pulmonary infection caused by long incision, which brought more advantages for overweight patients.
This study has some limitations. First, this was a retrospective, non-randomized survey that may have suffered from selection bias. Second, this was a single-center study and there is still no standard treatment for liver cancer. Our results might have been in uenced by our surgical strategy. Thirdly, we only used BMI to estimate obesity, which was not enough to assess the abdominal adiposity of Asian people.

Conclusion
Our data showed that laparoscopic approach to treat overweight patients with hepatocellular carcinoma is feasible and safe. Overweight has a proactive effect for perioperative complications and tumor occurrence and it should not deter a surgeon for selection the LH for patients with liver malignance.

Declarations
Ethics Approval and consent to participate This study was reviewed and approved by the institutional Ethical Board of Sir Run Run Shaw Hospital of Zhejiang University. And the need for informed consent was waived due to the retrospective nature of the study.

Consent for publication
Not applicable

Availability of data and materials
The datasets generated and analyzed during the current study are available from the corresponding author.

Competing interests
The authors declare that they have no competing interests and no nancial relationship with other organizations sponsoring this research.

Funding
The work was supported by the fund of public health bureau of Zhejiang Province (2016KYA152) which was awarded to Dr. Zheng Xing.
The funding sources have no role in study design, data collection, analysis, interpretation and the writing of the manuscript.

Authors' Contributions
ZL performed the statistical analysis and drafted the manuscript. WJG and ZX conducted the study and managed the database. KJX performed critical revision of manuscript. YX participated in its design and drafted the manuscript. All authors have read and approved the nal manuscript. Overall survival for all patients in elderly group (solid line) and in younger group (dashed line)

Supplementary Files
This is a list of supplementary les associated with this preprint. Click to download. BMI.xlsx