Approach Considerations
Complete surgical resection is the only therapy to afford a chance of cure for cholangiocarcinoma. Unfortunately, many patients present with unresectable disease. Additional treatment measures in cholangiocarcinoma may include the following [8] :
-
Stenting
-
Photodynamic therapy (PDT)
-
Radiation therapy
-
Pharmacotherapy
For palliative treatment, celiac-plexus block via regional injection of alcohol or other sclerosing agent can relieve pain in the mid back from retroperitoneal tumor growth. In addition, other endoscopic forms of palliation, such as brachytherapy and radiofrequency ablation, have been used. [28, 29, 30]
Stent Placement
Stents can be placed via endoscopic retrograde cholangiopancreatography (ERCP) or percutaneous transhepatic cholangiography (PTC) to relieve biliary obstruction. Stenting may relieve pruritus and improve quality of life.
Stents usually are used if the tumor is unresectable or if the patient is not a surgical candidate. Debate exists about whether preoperative stenting is warranted, but most surgeons believe that preoperative biliary decompression does not alter the outcome of surgery.
Either plastic or metal stents may be used. Plastic stents usually occlude in 3 months and require replacement. Metal stents are more expensive but expand to a larger diameter and tend to stay patent longer. Adequate biliary drainage can be achieved in a high percentage of cases. A study by Kida et al found that covered biliary self-expandable metal stents could be safely removed when they become occluded and that patency rates were similar for reintervention and initial stent placement. [31]
Photodynamic Therapy
Photodynamic therapy (PDT) is an experimental local cancer therapy already in use for other gastrointestinal malignancies. [32, 33] PDT is a two-step process: the first step is intravenous (IV) administration of a photosensitizer; the second step is activation by light illumination at an appropriate wavelength. [32, 33]
PDT is effective in restoring biliary drainage and improving quality of life in patients with nonresectable disseminated cholangiocarcinomas. Survival times may be longer than those reported previously. A prospective, multicenter study showed a significant survival benefit in the PDT treatment group. [32] An additional multicenter study is being planned.
Radiation Therapy
Adjuvant and preoperative radiation therapy has been used to reduce tumors in an effort to make them resectable. This therapy has been performed with and without concurrent chemotherapy as a radiation sensitizer.
Adjuvant radiotherapy has been to improve local control, with variable effect on overall survival after complete resection. Several series have shown an increase in median survival duration with postoperative radiation, from 8 months with surgery alone to more than 19 months.
Special radiation techniques have been used, such as intraluminal brachytherapy and external-beam therapy during surgery (ie, intraoperative radiotherapy [IORT]). See the image below for treatment planning technique.
Three-dimensional treatment planning uses CT scan slices to reconstruct the patient as a volume. Shown here is the display for planning external-beam radiotherapy to the cholangiocarcinoma (green structure). A biliary catheter (red tube) runs through the tumor volume and was used to deliver brachytherapy, which was given in addition to external-beam radiotherapy. Such technology has assisted greatly in the delivery of high doses to the tumor, while sparing vital normal structures, such as the kidney and spinal cord.
In patients with medially inoperable or unresectable tumors, primary radiotherapy, with or without chemotherapy, has provided a survival advantage and significant palliation over stent placement or bypass surgery alone. A study of 66 patients with unresectable intrahepatic cholangiocarcinoma treated with hypofractionated radiation therapy reported 2-year outcomes of 84% local control and 58% overall survival. [34]
In a study of 1636 patients with unresectable localized intrahepatic cholangiocarcinoma, the addition of radiation to chemotherapy was associated with an improvement in overall survival. Two-year overall survival was 20% for the chemotherapy-alone cohort versus 26% for the chemoradiation therapy group. [35]
Radioembolization with yttrium-90 has been shown to be safe and effective in patients with unresectable/recurrent intrahepatic cholangiocarcinoma. Mosconi et al reported significantly longer survival in patients who received radioembolization as initial therapy, compared with patients in whom radioembolization was preceded by other treatments, including surgery (52 vs 16 months, P=0.009). [36]
Pharmacotherapy
Chemotherapy
Most often, chemotherapy is given in low doses to act as a radiation sensitizer during a 4- to 5-week course of external-beam radiotherapy. Primary chemotherapy has been evaluated as well, including gemcitabine and cisplatin as first-line chemotherapy in inoperable biliary tract carcinoma. [37, 38] However, chemotherapy agents used without radiotherapy or surgery do not appear to provide any local control or meaningful survival benefit.
The most used agent has been 5-fluorouracil, which has a partial response rate of about 12%. Gemcitabine has a similar response rate. Although fluoropyrimidines and doxorubicin have been reported to have response rates as high as 30-40%, partial responses lasting from weeks to months have been observed in only 10-35% of trials. [37, 38]
A systematic review and meta-analysis found a significant improvement in overall survival with any adjuvant chemotherapy after cholangiocarcinoma surgery compared with surgery only (hazard ratio [HR] 0.74; 95% CI, 0.67 to 0.83; P < 0.001). The benefit of adjuvant therapy extended to patients with margin-positive surgery and node-positive disease. [39]
For patients with intrahepatic cholangiocarcinomas who have no residual local disease after resection, the National Comprehensive Cancer Network (NCCN) suggests observation or adjuvant gemcitabine-based chemotherapy. For lesions that are resected with microscopic margins or positive regional nodes, options include systemic therapy, fluoropyrimidine-based chemoradiation, fluoropyrimidine-based or gemcitabine-based chemotherapy followed by fluoropyrimidine-based chemoradiation, and fluoropyrimidine-based chemoradiation followed by fluoropyrimidine-based or gemcitabine-based chemotherapy. [40]
No data support a specific surveillance schedule. However, the NCCN suggests considering multiphasic abdominal/pelvic computed tomography (CT)/magnetic resonance imaging (MRI) with contrast and chest CT with contrast every 3–6 mo for 2 y, then every 6–12 months for up to 5 years, or as clinically indicated. [40]
For intrahepatic cholangiocarcinoma with residual local disease after resection, NCCN suggestions include systemic therapy, external beam radiation therapy (EBRT) with concurrent fluoropyrimidine, or best supportive care. The choice of care may be guided by the extent and/or location of disease and institutional capabilities. [40]
For unresectable extrahepatic cholangiocarcinoma, NCCN options include biliary drainage if indicated, biopsy for molecular testing of the tumor, or referral for transplantation. Subsequent primary treatment may consist of systemic therapy (with gemcitabine plus cisplatin being the preferred regimen), EBRT with concurrent fluoropyrimidine, palliative EBRT, or best supportive care. For metastatic extrahepatic cholangiocarcinoma, biliary drainage if indicated or biopsy for molecular testing of the tumor may be followed by systemic therapy or best supportive care. [40]
Targeted Therapy
Targeted agents are becoming available as second-line therapy for cholangiocarcinoma with specific driver mutations. These include fibroblast growth factor receptor 2 (FGFR2)–selective tyrosine kinase inhibitors for advanced cholangiocarcinoma harboring an FGFR2 gene fusion or rearrangement, and an isocitrate dehydrogenase 1 (IDH1) inhibitor for IDH1-mutated cholangiocarcinoma.
Futibatinib
The US Food and Drug Administration (FDA) approved futibatinib (Lytgobi) in October 2022 for treatment of adults with previously treated, unresectable, locally advanced or metastatic intrahepatic cholangiocarcinoma harboring FGFR2 gene fusions or other rearrangements. Approval was based on results of FOENIX-CCA2, a global phase 2 open-label trial in which 103 patients received futibatinib 20 mg/day PO until disease progression or unacceptable toxicity. The objective response rate was 41.7% and the median duration of response was 9.5 months, with 74% of responses lasting at least 6 months. [41]
Pemigatinib
In 2020, the FDA approved pemigatinib (Pemazyre) for previously treated, unresectable, locally advanced or metastatic cholangiocarcinoma with an FGFR2 fusion or other rearrangement as detected by an FDA-approved test. Pemigatinib is a small molecule kinase inhibitor that targets FGFR1, 2, and 3 by inhibiting FGFR1-3 phosphorylation and signaling. FGFR inhibition disrupts tumor cell proliferation, survival, migration, and angiogenesis.
Approval was supported by the FIGHT-202 study, which included 107 patients with FGFR2 fusions or rearrangements, 20 with other alterations in FGF/FGFR, 18 with no alterations, and 1 with an undetermined alteration. Thirty-eight (35.5%) of the 107 patients with FGFR2 fusions or rearrangements achieved an objective response (3 complete responses; 35 partial responses) to pemigatinib treatment. [42]
Infigratinib
Infigratinib is indicated for adults with previously treated, unresectable, locally advanced or metastatic cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion or other rearrangement. It is an orally bioavailable inhibitor of FGFR types 1, 2, and 3 phosphorylation and signaling, and thereby decreases cell viability in cancer cell lines with activating FGFR amplifications and fusions.
Accelerated approval was granted by the FDA in May 2021 based on results from a single-arm, phase 2 trial. Among 108 patients, 83 (77%) had FGFR2 fusions. The overall response rate (ORR) was 23.1% including 1 complete response complete response and 24 partial responses. Median duration of response (DOR) was 5 months (range 0.9–19.1 months). Among responders, 8 (32%) patients had a DOR of 6 months or greater. Median progression-free survival was 7.3 months. Subgroup analysis included an ORR of 34% (17/50) in the second-line setting and 13.8% (8/58) in the third-/later-line setting (3-8 prior treatments). [43]
Ivosidenib
In August 2021 the FDA approved ivosidenib (Tibsovo) for treatment of adults with previously treated locally advanced or metastatic IDH1-mutated cholangiocarcinoma. Ivosidenib was previously approved for use in IDH1-mutated acute myeloid leukemia. Approval of ivosidenib for cholangiocarcinoma was based on findings from the randomized phase III ClarIDHy trial in which 70.5% of patients in the placebo group crossed over to ivosidenib at the time of progression as permitted by the study protocol.
The primary efficacy endpoint was progression-free survival (PFS); the trial demonstrated a statistically significant improvement in PFS for patients randomized to ivosidenib (HR, 0.37; P < .0001).
[44]
Surgical Care
Complete surgical resection is the only therapy to afford a chance of cure. Unfortunately, only 10% of patients present with early-stage disease and are candidates for curative resection. Intrahepatic and Klatskin tumors [7] require liver resection, which may not be an option for older patients with comorbid conditions. In one report, 15% of patients with proximal lesions were candidates for complete resections, with higher rates in patients with mid-ductal tumors (33%) or distal tumors (56%). The survival rate for patients with proximal tumors can be 40% if negative margins are obtained.
Orthotopic liver transplantation is considered for some patients with proximal tumors who are not candidates for resection because of the extent of tumor spread in the liver. The largest series reports a 53% 5-year survival rate and a 38% complete pathologic response rate with preoperative radiation therapy and chemotherapy. Liver transplantation may have a survival benefit over palliative treatments, especially for patients with tumors in the initial stages. One study has demonstrated a 5-year survival rate greater than 80% in select patients. [45]
Distal tumors are resected via Whipple procedure; periampullary region tumors have a uniformly better prognosis, with a long-term survival rate of 30-40%.
Patterns of treatment failure after curative surgery show disappointingly high rates of tumor bed and regional nodal recurrence. This finding may be due in part to the narrow pathologic margins; however, the regional node failure rate is approximately 50%, and the distal metastases rate is 30-40%. Failure rates correlate with TNM stage. Adjuvant transcatheter arterial chemoembolization for intrahepatic cholangiocarcinoma has been used post attempted curative surgery, with better survival in patients with early recurrence. [46]
Palliative procedures are required if internal stenting cannot be accomplished and/or external stenting is not desirable or cannot be obtained. Surgical bypass, particularly for tumors in the common bile duct, should be performed in such cases.
Consultations
Gastroenterologists, interventional radiologists, and transplant/biliary surgeons play a key role in diagnosis and management. Radiation oncology and medical oncology specialists are part of the multidisciplinary team taking part in the treatment of both patients with curatively resected tumors and those with unresectable tumors. Radiation oncologists have taken a more significant role in therapy for cholangiocarcinomas since the early 1980s.
-
Bismuth classification for perihilar cholangiocarcinoma. Shaded areas represent tumor location.
-
Tight stricture of a common hepatic duct in a patient presenting with jaundice. Cytologic studies confirmed cholangiocarcinoma.
-
Three-dimensional treatment planning uses CT scan slices to reconstruct the patient as a volume. Shown here is the display for planning external-beam radiotherapy to the cholangiocarcinoma (green structure). A biliary catheter (red tube) runs through the tumor volume and was used to deliver brachytherapy, which was given in addition to external-beam radiotherapy. Such technology has assisted greatly in the delivery of high doses to the tumor, while sparing vital normal structures, such as the kidney and spinal cord.
Tables
T - Primary tumor |
|||
TX |
Primary tumor cannot be assessed |
||
T0 |
No evidence of primary tumor |
||
Tis |
Carcinoma in situ (intraductal tumor) |
||
T1 |
Solitary tumor without vascular invasion, ≤5 cm or > 5 cm |
||
T1a |
Solitary tumor ≤5 cm without vascular invasion |
||
T1b |
Solitary tumor > 5 cm without vascular invasion |
||
T2 |
Solitary tumor with intrahepatic vascular invasion, or multiple tumors with or without vascular invasion |
||
T3 |
Tumor perforating the visceral peritoneum |
||
T4 |
Tumor involving local extrahepatic structures by direct invasion |
||
N – Regional lymph nodes |
|||
NX |
Regional lymph nodes cannot be assessed |
||
N0 |
No regional lymph node metastasis |
||
N1 |
Regional lymph node metastasis present |
||
M – Distant metastasis |
|||
M0 |
No distant metastasis |
||
M1 |
Distant metastasis present |
||
T - Primary tumor |
|||
TX |
Primary tumor cannot be assessed |
||
T0 |
No evidence of primary tumor |
||
Tis |
Carcinoma in situ – high-grade dysplasia |
||
T1 |
Tumor confined to the bile duct, with extension up to the muscle layer or fibrous tissue |
||
T2 |
Tumor invades beyond the wall of the bile duct to surrounding adipose tissue, or tumor invades adjacent hepatic parenchyma |
||
T2a |
Tumor invades beyond the wall of the bile duct to surrounding adipose tissue |
||
T2b |
Tumor invades adjacent hepatic parenchyma |
||
T3 |
Tumor invades unilateral branches of the portal vein or hepatic artery |
||
T4 |
Tumor invades main portal vein or its branches bilaterally, or the common hepatic artery; or unilateral second-order biliary radicals bilaterally with contralateral portal vein or hepatic artery involvement |
||
N – Regional lymph nodes |
|||
NX |
Regional lymph nodes cannot be assessed |
||
N0 |
No regional lymph node metastasis |
||
N1 |
One to three positive lymph nodes typically involving the hilar, cystic duct, common bile duct, hepatic artery, posterior pancreatoduodenal, and portal vein lymph nodes |
||
N2 |
Four or more positive lymph nodes from the sites described for N1 |
||
M – Distant metastasis |
|||
M0 |
No distant metastasis |
||
M1 |
Distant metastasis |
||
T - Primary tumor |
|
TX |
Primary tumor cannot be assessed |
T0 |
No evidence of primary tumor |
Tis |
Carcinoma in situ – high-grade dysplasia |
T1 |
Tumor invades the bile duct wall with a depth less than 5 m |
T2 |
Tumor invades the bile duct wall with a depth of 5–12 m |
T3 |
Tumor invades the bile duct wall with a depth greater than 12 mm |
T4 |
Tumor involves the celiac axis, superior mesenteric artery, and/or common hepatic artery |
N – Regional lymph nodes |
|
NX |
Regional lymph nodes cannot be assessed |
N0 |
No regional lymph node metastasis |
N1 |
Metastasis in 1-3 regional lymph nodes |
N2 |
Metastasis in ≥4 regional lymph nodes |
M – Distant metastasis |
|
M0 |
No distant metastasis |
M1 |
Distant metastasis |
Intrahepatic bile duct tumor |
|||
Stage |
T |
N |
M |
0 |
Tis |
N0 |
M0 |
IA |
T1a |
N0 |
M0 |
IB |
T1b |
N0 |
M0 |
II |
T2 |
N0 |
M0 |
IIIA |
T3 |
N0 |
M0 |
IIIB |
T4 |
N0 |
M0 |
|
Any T |
N1 |
M0 |
IV |
Any T |
Any N |
M1 |
Perihilar bile duct tumor |
|||
Stage |
T |
N |
M |
0 |
Tis |
N0 |
M0 |
I |
T1 |
N0 |
M0 |
II |
T2a-b |
N0 |
M0 |
IIIA |
T3 |
N0 |
M0 |
IIIB |
T4 |
N0 |
M0 |
IIIC |
Any T |
N1 |
M0 |
IVA |
T4 |
N2 |
M0 |
IVB |
Any T |
Any N |
M1 |
Distal bile duct tumor |
|||
Stage |
T |
N |
M |
0 |
Tis |
N0 |
M0 |
I |
T1 |
N0 |
M0 |
IIA |
T1 |
N1 |
M0 |
|
T2 |
N0 |
M0 |
IIB |
T2 |
N1 |
M0 |
|
T3 |
N0 |
M0 |
|
T3 |
N1 |
M0 |
IIIA |
T1-3 |
N2 |
M0 |
IIIB |
T4 |
N0-2 |
M0 |
IV |
Any T |
Any N |
M1 |
