METHODS

The structure of this systematic review followed the PRISMA guidelines.13

Information sources and search strategy


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For all studies, a literature search was conducted using MeSH keyword search on PubMed (MEDLINE), which matched the eligibility criteria as mentioned earlier. An additional manual search of OVID (MEDLINE) was carried out. All identified articles discussing about adjuvant strategies for cholangiocarcinoma were retrieved from those databases.

These studies were restricted to those in English language. The search period was restricted to be more representative of modern postoperative outcomes.

Treatment of localized cholangiocarcinomas: resection first

The establishment of the exact criteria for resectability in patients with cholangiocarcinoma has several limitations. Many factors should be taken into account: the patient’s clinical condition and comorbidities, the biology of the neoplasia, the technical expertise of the surgeon, local involvement of the major vessels and bile ducts at the hilum, future liver remnant, etc.14

Although the establishment of resectability criteria has many limitations, the patient must be medically fit for resection, the presence of metastatic disease should be ruled out, and the local involvement of the main tumor mass should be assessed very carefully with attention to vascular inflow, outflow, hepatic parenchyma, and the biliary tree. If the portal vein, hepatic artery, or secondary biliary tree is involved, the tumor is considered as not resectable. In some cases, minimal portal vein involvement can be resected and cleared if far enough away from the umbilical fissure.15

Surgical resection generally includes cholecystectomy, en bloc hepatic resection, and lymphadenectomy with or without bile duct excision, depending on the location of the tumor. If cancer is found incidentally at the time of surgery for other reasons, resectability is not clearly established, then delayed open laparotomy is appropriate, as there is no survival deficit compared to immediate resection.16,17

In all the cases, the liver remnant should be at least 30% of the liver volume of relatively normal nonatrophied parenchyma that should have a good vascular inflow, outflow, and biliary drainage.

The decision about resectability for patients with distal cholangiocarcinoma is more straightforward than that for those with perihilar and peripheral tumors.15

For the peripheral tumors, if the lesion is away from the hilus of the liver and does not involve a significant proportion of parenchyma, the determination of resectability would be less complicated than for central or very large tumors.17

Generally for cholangiocarcinomas, the overall rate of resectable disease is only 10–40%2,5 and an operative mortality of 4% has been reported for peripheral cholangiocarcinomas.15

For hilar cholangiocarcinoma, the 30- and 90-day operative mortalities have been shown to be 10 and 12%, respectively. The overall incidence of postoperative morbidity was 69%. In all, 68% of them were described as major. No difference in operative blood loss or perioperative transfusion rates was observed for patients with major versus minor or no postoperative morbidity. Patients with major postoperative morbidity received adjuvant chemotherapy in less number of cases when compared with those with minor postoperative morbidity or no complications 29 versus 52%.19

Although removal of clinically suspicious nodal disease is mandatory, the role of routine lymphadenectomy is not well defined. Lymph node dissection is not routinely performed at the time of ICC resection in most Western countries as opposite to many Japanese hospitals. In Western series, only 50% of the patients had at least one lymph node examined, and more relevant was the fact that among these patients, metastatic nodal disease was found in up to 30% of patients.18

This is the reason why some researchers have defended the role of routine lymphadenectomy as this will impact on prognosis.20

Many surgeons will pursue resection, despite local lymph node metastases, whereas distant lymph node metastases are a contraindication to surgery.

Despite this finding, Shimada et al concluded that routine lymphadenectomy was not necessary if lymph node involvement was not clinically apparent. Their study showed that among those patients who underwent lymphadenectomy, there were no differences in survival if lymph node was not involved regardless of the use of lymph node dissection.21

Rate of recurrence is about 50–60%, and the median disease-free survival has been documented as 26 months. Five-year survival and overall survival (OS) after surgical resection of ICC range from 15 to 40% in most series.21,22

Liver is the most common site of recurrence (50–60%), but recurrence in regional lymph nodes or the peritoneum has also been documented in 20–25%.23–25 Other series mention 23–63%.26–28

One of the factors associated with an increased risk of recurrence include lymph node metastasis and also tumor size, multiple tumors, and vascular invasion.29

The ICCs are relatively rare, but their incidence and mortality are increasing worldwide.30

The only potentially curative treatment option for patients who have resectable disease is surgery as for the rest but again and unfortunately, the five-year survival rate is about 20–35%.31,32

Moreover, the role of adjuvant therapies, including systemic chemotherapy and radiotherapy, remains poorly defined and has been reported to have only a modest therapeutic effect.

Routine staging laparoscopy has been proposed because high incidence of metastatic disease has not been detected by conventional imaging.33

Lymphadenectomy is also not routinely performed in most Western countries, despite data suggesting that lymph node status may provide considerable prognostic information.34,35