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Differences of intraoperative outcomes and postoperative complications between intrahepatic cholangiocarcinoma and colorectal liver metastasis in different surgical methods

Background Hepatectomy is the only potentially curable treatment for intrahepatic cholangiocarcinoma (IHCC) and colorectal liver metastasis (CRLM). This study aimed to explore the difference in intraoperative outcomes and postoperative complications between IHCC and CRLM in different surgical methods including major hepatectomy and minor hepatectomy. Methods We included 319 patients with IHCC or CRLM who underwent hepatectomy at our hospital. According to major hepatectomy and minor hepatectomy, eligible patients were divided into two groups. In each group, the clinicopathological characteristics of IHCC and CRLM patients were compared, then propensity score matching (PSM) was performed based on the results. Intraoperative outcomes and postoperative complications were compared between IHCC and CRLM before and after PSM. Intraoperative variables, including intraoperative blood transfusion, duration of operation, and intraoperative blood loss, were used to evaluate the intraoperative conditions of patients. The postoperative complications were measured according to the Clavien-Dindo classification. Grade III to V complications were defined as major complications. Results The major hepatectomy group included 118 patients with IHCC and 93 patients with CRLM. IHCC patients presented a longer operation time and a higher postoperative complication rate than CRLM patients. The infection-related complication rate of the CRLM patients was significantly higher than the IHCC patients. In multivariate analysis, major hepatectomy for IHCC was independently associated with the presence of postoperative complications. The minor hepatectomy group included 146 IHCC patients and 62 CRLM patients. Compared with CRLM patients, IHCC patients presented a longer operation time. There was no significant difference in the intra-operative blood loss, postoperative complication rate, the major complications rate, and the minor complications rate between the IHCC patients and CRLM patients. Conclusions This study revealed major hepatectomy for IHCC led to significantly higher morbidity of postoperative complications than CRLM patients. For minor hepatectomy, there was no difference in postoperative complications between IHCC and CRLM. More attention should be paid to improving the preoperative planning and surgical management of hepatic malignancies especially in the setting of IHCC.


Introduction
Nowadays, surgery is the only potentially curable treatment for common hepatic malignancies, including intrahepatic cholangiocarcinoma (IHCC) (1) and colorectal liver metastasis (CRLM) (2). For IHCC, radical surgery including hepatectomy and lymph node dissection only achieved a 5-year survival rate of 30% (3). For CRLM, all patients with curable potentials were recommended to receive surgical treatment. The 5-year survival rate after hepatectomy ranged from 20% to 45% (4,5). The basic condition for radical resection is to achieve R0 resection (6)(7)(8)(9), which requires extended and complex hepatectomies (10). Hepatectomy is mainly divided into major and minor hepatectomy according to the extent of hepatectomy. Resection of three or more liver segments is defined major hepatectomy, which may facilitate the radical resection. However, perioperative morbidity and mortality may be higher than minor resection because of the wider surgical margin and removal of portal tributaries (11).
Patients with heterogeneous CRLM need to receive primary lesion radical resection firstly, hence when it came to second surgery for liver metastasis, abdominal adhesions might increase the probability of postoperative complications (12). Operations for different types of hepatic malignancy have different risk factors for postoperative complications. The most serious postoperative complication is liver failure caused by preoperative damaged liver function and cirrhosis, especially for IHCC patients (7). The increasing rate of postoperative complications leads to prolonged postoperative recovery time, increasing economic burden, and worse long-term prognosis of patients (13).
The preoperative liver function status and expected outcomes after hepatectomy for IHCC or CRLM were similar, but the postoperative mortality and morbidity rates were different. Compared with CRLM, IHCC presented worse mortality (0-2% vs. 6-10%) and morbidity (16-32% vs. 48-50%) (14)(15)(16)(17). The differences under the same conditions of hepatectomy may be due to the specific characteristics of diseases and surgical management. Zhang et al. (15) found that major hepatectomy for IHCC was not associated with an overall survival benefit, yet was associated with increased perioperative morbidity. For CRLM, more and more researchers recommended promoting parenchyma-sparing hepatectomy (18,19). Because it substantially decreased intraoperative blood loss and postoperative liver failure (20). Doussot et al. (10) suggested that IHCC patients were at higher risk inherently after major hepatectomy compared with CRLM patients. One possible reason was the higher frequency of portal lymphadenectomy for IHCC. Vascular and biliary injury are difficult to avoid and may result in some complications such as, lymphatic leakage, biliary ischemia, or bleeding. Better perioperative and operative management can translate into reducing mortality and morbidity. A better understanding of these differences may help improve perioperative management and thus patient outcomes, but no comprehensive comparative studies have been conducted.
The above observations motivated the current study. This study was conducted to explore the differences in intraoperative outcomes and postoperative complications between IHCC and CRLM in different surgical methods. The propensity score matching (PSM) was used to eliminate the significant differences in preoperative, intraoperative, and postoperative data. We present the following article in accordance with the STROBE reporting checklist (available at https://dx.doi.org/10.21037/tcr-21-553). Medical Sciences (ID NCC2019C-016). Informed consent was taken from all the patients.

Data collection
This was a retrospective study based on the CRLM and HICC datasets. Clinical variables included age, gender, American Society of Anesthesiology (ASA) score, body Mass Index (BMI), and preoperative test markers. Tumor-related variables included tumor size and number. Eligible patients were divided into two groups according to major hepatectomy and minor hepatectomy. The clinical covariates of patients with IHCC and CRLM were compared between the two groups to find differences between the two groups. In each group, PSM was performed based on the results. The primary outcomes included intraoperative variables and postoperative complications. The primary objective of this study was to compare the differences in intraoperative variables and postoperative complications between IHCC and CRLM patients, with a secondary objective to identify independent risk factors for postoperative complications in these patients. Compared with CRLM patients, IHCC patients received significantly more frequent lymphadenectomy (76.3% vs. 0.0%, P<0.001) and less preoperative treatment (7.6% vs. 67.7%, P<0.001). Based on the significant distribution difference of preoperative treatment and lymphadenectomy (PTL) between those patients. The combination of the PTL on these two factors was constructed to eliminate the influence of the two on the outcomes and ensure the feasibility of PSM. The PTL was scored as 0 (nonpreoperative treatment with non-lymphadenectomy), 2 (preoperative treatment with lymphadenectomy), and 1 (all other combinations). Intraoperative variables, including intraoperative blood transfusion, duration of operation, and intraoperative blood loss, were used to evaluate the intraoperative conditions of patients. The postoperative complications were measured according to the Clavien-Dindo classification. Grade III to V complications were defined as major complications. If patients experienced multiple postoperative complications, the highest grade was used. The postoperative complications included general complications and surgical-related complications. Death or complications within 30 days after surgery are considered postoperative mortality and morbidity.

Statistical analysis
The Mann-Whitney U test was performed to analyze continuous variables, including operation time and intraoperative blood loss, etc. The Chi-square or Fisher's exact test was used to analyze categorical variables. The independent predictive factors of postoperative complications were identified using univariable and multivariable logistic regressions. For patients undergoing the same type of hepatectomy, the PSM method was used to balance the imbalanced clinicopathological characteristics between IHCC and CRLM patients. In patients receiving major hepatectomy, age, preoperative serum gamma glutamyl transpeptidase (GGT) level, the diameter of the largest tumor, and tumor number were balanced. In patients receiving minor hepatectomy, ASA, the diameter of the largest tumor and PTL were balanced. Patients with ICHCC were matched in a 1:1 ratio to patients with CRLM, with a standard caliper width of 0.2. A two-tailed P value of less than 0.05 was considered significant. The SPSS version 22.0 software (Armonk NV, USA) and R software (http://www.r-project.org, 3.6.3) were used to perform the statistical analyses.

Results
In this study, 319 patients were included, including 164 IHCC patients and 155 CRLM patients. There were 118 IHCC patients and 93 CRLM patients undergoing major hepatectomy, respectively. Forty-six IHCC patients and 62 CRLM patients receiving minor hepatectomy, respectively. The outcomes were compared between HICC and CRLM patients in each group.

Discussion
Our study found that intraoperative outcomes and the         the infection-related complication rate was significantly higher in the CRLM patients than in the IHCC patients. For minor hepatectomy, there was no significant difference in postoperative complications between IHCC and CRLM. The operative time of IHCC patients was longer whatever in the major or minor hepatectomy group. Early postoperative complications commonly seen in patients with hepatectomy are postoperative bleeding, ascites, infection, and liver failure. Liver failure is the most serious one of them, resulting in postoperative mortality (21,22). The incidence of complications in this study reached 53.9%, including 65.4% in major and 31.5% in minor hepatectomy. The most common complication in our study was infection. CRLM patients were more likely to develop infection-related complications during major hepatectomy, which might be related to preoperative adjuvant therapy and secondary surgery. Besides, obesity has been implicated as a risk factor for the development of all-stage colorectal cancer by affecting insulin pathways (23,24). More than 60% of patients with CRLM had a BMI ≥24 kg/m 2 in this study. And CRLM patients are more likely to have postoperative hyperglycemia (25). Previous studies indicated patients who developed postoperative hyperglycemia after colorectal operations had an increased risk of infection (26,27). Surgical complications, such as postoperative bleeding and deep venous thrombus, were not different between IHCC and CRLM. In patients who underwent hepatectomy, bile leakage remained a common cause of postresectional liver failure (28), with an incidence of 3.4-12.9% (29,30). However, the morbidity of bile leakage in IHCC patients was not higher than CRLM, though peripheral bile duct dilatation and lymph node dissection were more common in IHCC.
The incidence of postoperative complications between different types of hepatic malignancies was not compared comprehensively in most other centers. In our study, the morbidity of overall complications in the IHCC group was significantly higher the CRLM group. Even after PSM, the rate remained high. And major hepatectomy was a risk factor for the postoperative complication in IHCC group, but not in the CRLM group. Postoperative complications might be not only related to the range of hepatectomy but also the type of hepatic malignancy. In other words, IHCC patients might be inherently at higher operative risk as compared to CRLM patients, possibly due to the biology of the tumor.
Multiple studies have proven that postoperative complications were related to the operation time (10,31,32).
Longer operative time and greater bleeding volume increased the risk of post-hepatectomy morbidity and mortality in both open and laparoscopic hepatectomy (14,15). In this study, the operation time of IHCC was longer than CRLM. Biliary and vascular resections was more common in the surgery of IHCC, which need longer operative time. The location of IHCC always close to the porta hepatis and the retrohepatic inferior vena cava and the tumor size of IHCC was significantly bigger. Another possible reason was routine lymph node dissection for IHCC, while it was not performed routinely for CRLM. Therefore, longer operative time were associated with the characteristics of IHCC.
When patients received major hepatectomy, the morbidity of postoperative complications in IHCC was higher than CRLM. But when they received a minor one, there was no significant difference. It was not surprising because the vascular and biliary injury may be inevitable and the injury can lead to specific postoperative complications such as biliary ischemia or lymphatic leak during portal lymphadenectomy (10). In other studies, age, preoperative liver function Child-Pugh score, range of hepatectomy, and intraoperative bleeding were independent risk factors for postoperative complications of hepatic malignancies (20,(33)(34)(35)(36).
Our study did have some limitations. First, it was retrospective and single-institutional. Second, there was no other center to validate our conclusion. In the future, we hope there will be more studies to verify the results. Despite these limitations, this study may lead to some comprehensive understanding of these differences. First, considering that in the study the operation for CRLM was secondary surgery, it would take a longer time than the first operation. Both IHCC and CRLM pursued R0 resection, IHCC did not specifically emphasize the extension of the range of hepatectomy compared to CRLM. Previous studies did not clarify the cases of simultaneous and heterogeneous CRLM, nor did they compare the cases of preoperative adjuvant therapy. We took this into account and only heterogeneous CRLM were selected. Second, the rate of complication could also be related to lymph node dissection for IHCC (37) or preoperative neoadjuvant treatment for CRLM (38). Preoperative neoadjuvant chemotherapy was common for CRLM, but only a small percentage of patients with IHCC received preoperative neoadjuvant chemotherapy. Hence no matter which of the two was matched in PSM, the size of the other group would be too small. In this case, the combination of the status of PTL was established to analyze the postoperative complications.
In conclusion, our study confirmed that major hepatectomy for IHCC led to significantly higher morbidity of complications than CRLM patients. Nowadays, the oncological resection of tumors remains the gold standard for therapeutic intents, so more attention should be paid to improve surgical techniques and management of hepatic malignancies especially in the setting of IHCC, which will lead to a favorable outcome after surgery.