Isolated locoregional failure rate (%)
Initial distant failure rate (%)
Extrahepatic/hilar cholangiocarcinoma
Surgery alone
4–34
24–40
+adjuvant chemoradiotherapy (SWOG 0809)
8
29
Gallbladder cancer
Surgery alonea
3–33
15–51
+adjuvant chemoradiotherapy (SWOG 0809)
0
44
11.6.1 Extrahepatic Cholangiocarcinoma Patterns of Failure
In a retrospective study of 306 patients with hilar cholangiocarcinoma treated with primary surgery (8 % received adjuvant chemotherapy; 8 % received adjuvant radiotherapy), 58 % recurred. Only 18 % of patients had an isolated initial local recurrence (at the liver hilum, hepaticojejunostomy, liver resection margin, or distal bile duct remnant). Another 8 % of patients had a local recurrence that occurred synchronously with a distant recurrence. The majority of recurrences (69 %) included initial distant recurrences (retroperitoneal lymph nodes, distant intrahepatic site, peritoneum, or lungs) [19].
Recurrence rates for hilar cholangiocarcinomas after curative intent resection ranged from 49–66 % across 6 studies, while only 4–18 % of patients had an isolated local recurrence [19].
Another large retrospective study including 76 evaluable patients with hilar cholangiocarcinoma reported a recurrence rate of 68 %. Eighteen of all 76 patients (24 %) recurred initially at a distant site (site of first disease recurrence was not definitively known in 8 patients). In contrast, 26 of 76 patients (34 %) had an isolated locoregional failure (including tumor bed, porta hepatis, and retroperitoneal lymph nodes) [52].
Results of the prospective SWOG 0809, in which all patients had adjuvant chemoradiotherapy in addition to curative intent surgery, indicated a low rate of isolated local recurrence for patients with hilar cholangiocarcinoma (1 of 13 patients, 8 %). A total of 4 of 13 patients (31 %) with hilar cholangiocarcinoma recurred [24].
11.6.2 Gallbladder Cancer Patterns of Failure
The retrospective analysis by Jarnagin et al. included 80 patients with gallbladder cancer treated with primary surgery (only 14 % received adjuvant therapy). The authors reported a recurrence rate of 66 % [52]. Distant recurrence was the predominant pattern of failure; the initial recurrence was at a distant site in 41 of 80 patients (51 %, first site of recurrence was not definitively known in five patients). Only 7 of 80 patients (9 %) suffered an isolated local failure. Interestingly, recurrences in patients with gallbladder cancer occurred earlier than recurrences in patients with hilar cholangiocarcinoma, a finding also observed in SWOG 0809.
In a retrospective study of 163 patients with incidental findings of gallbladder cancer (127 of whom underwent re-resection), only 6 patients (4 %) received adjuvant radiotherapy, whereas 31 % received adjuvant chemotherapy. In this context, approximately 20 % of patients recurred at 2 years, 75 % of whom had an isolated distant failure compared to 12.5 % with an isolated local failure. The low recurrence rate may be partly due to inclusion of a significant number of patients with stage I/II disease (62 %). The presence of lymph node metastasis was the single predictor of disease-free survival on multivariate analysis and 25 % of muscle invasive (T1b) cases presented with lymph node metastases, suggesting that patients with T1b disease may benefit from radical resection including a radical lymphadenectomy [53].
In a subset of 78 patients with T3-T4 disease, the overall recurrence rate after surgical resection was higher (76 %). Only 33 % of all patients had an isolated hepatic (or local) recurrence, compared to 42 % with either an extrahepatic or combined hepatic and extrahepatic recurrence [29].
In contrast, of the 25 patients enrolled on SWOG 0809 with gallbladder cancer treated with definitive surgery and adjuvant chemoradiotherapy, 52 % had a recurrence after a median follow-up of 35 months. None of these recurrences were isolated local failures [24].
11.7 Rationale for Adjuvant Therapy
The high rates of locoregional and distant recurrence in gallbladder cancer and extrahepatic cholangiocarcinoma have led to the use of adjuvant chemotherapy, radiotherapy, and chemoradiotherapy to limit failure rates after surgery with the prospect of improving long-term outcomes including survival.
While there is no high-level evidence to support its use, adjuvant therapy is commonly administered given the propensity for these tumors to recur.
A randomized phase III study of adjuvant chemotherapy versus observation in pancreaticobiliary malignancies from Japan conducted between 1986–1992 included 139 patients with cholangiocarcinoma and 140 patients with gallbladder cancer. The authors reported improved 5-year survival with adjuvant chemotherapy (mitomycin C and 5-fulorouracil) in patients with gallbladder cancer. Although the survival difference was not observed in the cholangiocarcinoma group, the authors noted a trend toward improved disease-free survival with adjuvant chemotherapy [54].
SWOG 0809 is a recently published single-arm phase 2 study of adjuvant chemoradiotherapy after resection of gallbladder cancer and extrahepatic cholangiocarcinoma, which demonstrated feasibility of performing a prospective trial in a rare disease population and established baseline outcomes with a commonly used adjuvant approach [24]. See Sect 11.8 for details.
SWOG 0809 was published after many retrospective analyses of adjuvant radiotherapy and chemoradiotherapy in gallbladder cancer and extrahepatic cholangiocarcinoma, a few summarized below:
Kim et al. reported on 168 patients with extrahepatic biliary tract cancer who underwent resection [55]. Postoperative chemoradiation with concurrent 5-fluorouracil-based chemotherapy was administered to 115 of 168 patients. After a median follow-up of 33.8 months, the median survival was 36.4 months in the adjuvant treatment group, versus 27.9 months in the observation group, which was statistically significant on multivariate analysis (p=0.005). Likewise, locoregional failure was lower in the adjuvant treatment group on multivariate analysis (p=0.001).
In 2012, a systemic review and meta-analysis of adjuvant therapy in biliary tract cancer presented data on 20 studies between 1960 and 2010 involving 6712 patients with gallbladder and biliary tract tumors [56]. Adjuvant therapy (including chemotherapy, radiation, and chemoradiation) was associated with a borderline significant improvement in survival (p = 0.06). In patients who had undergone R1 resections, adjuvant radiation had a survival benefit (p=0.01).
In contrast, other series have been more equivocal in regard to benefit of adjuvant radiation therapy. Sagawa et al., reporting on patients with hilar cholangiocarcinoma who underwent surgical resection, did not reveal an overall survival benefit in a subset that received adjuvant radiation [57].
Population studies have not demonstrated a clear benefit with adjuvant radiotherapy. In a Surveillance, Epidemiology, and End Results (SEER) analysis by Shinohara et al., 4758 patients with extrahepatic cholangiocarcinomas treated with surgery or radiation between 1998 and 2003 were assessed for overall survival [58]. Although the median survival was 16 months in the surgery and radiation group compared to 9 months with surgery alone (p<0.0001), this did not hold after adjusting for potential confounders.
For gallbladder cancer, a study of 73 patients with stage I and II disease who underwent R0 resection reported that overall survival was statistically improved with adjuvant chemoradiation on multivariate analysis, adjusting for T and N stage, as well as pathologic diagnosis [59].
In summary, the poor outcomes with surgery alone, along with extensive retrospective and limited prospective data, suggest that adjuvant therapies should be strongly considered in patients with gallbladder cancer and extrahepatic cholangiocarcinoma.
11.8 Multidisciplinary Treatment by Presentation
Gallbladder cancer: incidental finding at time of cholecystectomy
If T1a: observe.
If ≥T1b or positive margin, needs further staging and treatment:
Obtain CT or MRI of the abdomen for local staging; consider MRCP.
CT chest to rule out distant metastasis.
If resectable, proceed with radical cholecystectomy, which includes hepatic resection, lymphadenectomy, and may require bile duct excision.
Imaging finding of a resectable gallbladder mass or extrahepatic cholangiocarcinoma
Evaluation and work-up:
Assess medical comorbidities and tolerance of hepatic resection.
Obtain CT or MRI of the abdomen for local staging; consider MRCP.
CT chest to assess for distant metastatic disease.
Obtain baseline CA 19–9, CEA.
If elevated bilirubin or jaundiced, evaluate for biliary drainage preoperatively.
Standard Approach:
Gallbladder Cancer
If resectable, proceed with diagnostic laparoscopy [60]. If negative, proceed with radical cholecystectomy, which includes resection of at least a rind of hepatic parenchyma (and often hepatic segmentectomy), lymphadenectomy, and may require bile duct excision.
Extrahepatic cholangiocarcinoma
For resectable disease, diagnostic laparoscopy can be considered in select patients at higher risk for distant metastasis [61].
For hilar cholangiocarcinoma, surgery requires resection of the involved extrahepatic biliary structures and hepatectomy (commonly, extended right hepatectomy or left hepatectomy), as well as a biliary-enteric anastomosis (choledocho- or hepaticojejunostomy).
Preoperative biliary drainage and/or portal vein embolization can be considered in select patients with hilar cholangiocarcinoma to decrease the likelihood of liver failure [62].
For distal extrahepatic cholangiocarcinoma, resection involves removal of the involved extrahepatic biliary ducts, usually with a pancreaticoduodenectomy and biliary-enteric anastomosis.
Alternative approach for select patients at select centers:
For extrahepatic (hilar) cholangiocarcinoma with disease confined to the primary site without nodal metastasis (includes patients with primary sclerosing cholangitis), consider neoadjuvant chemoradiotherapy (including brachytherapy) followed by orthotopic liver transplantation [63].
Selection criteria include patients with pathologically confirmed diagnosis of hilar cholangiocarcinoma or a lesion (< 3 cm diameter) on imaging causing biliary obstruction on cholangiography with malignant endoluminal brushings.
Neoadjuvant therapy involves external beam radiation with concurrent chemotherapy (bolus intravenous 5-fluorouracil) followed by transluminal brachytherapy with Iridium-192 delivered through biliary catheters. Patients are then treated with 5-fluorouracil or capecitabine until transplantation.
Patients then undergo a staging surgical procedure to rule out presence of pathologic lymphadenopathy.
Of 71 patients with unresectable cholangiocarcinoma on a transplant treatment protocol at the Mayo Clinic, 38 underwent transplantation, among whom 5-year survival was 82 % (or 58 % if calculated on an intent-to-transplant basis) [63]. Twelve transplant centers combined data and reported a 5-year survival rate of 53 % (intent-to-treat analysis) [64]. Of transplanted patients, 65 % remained disease-free. Drop-out rate from transplant was 25 %.
Adjuvant therapy after surgical resection of gallbladder cancer or extrahepatic cholangiocarcinoma:
Strongly consider adjuvant therapy in all patients with gallbladder cancer except T1aN0M0 gallbladder cancer (see Sect 11.6). Strongly consider adjuvant therapy in all patients with extrahepatic cholangiocarcinoma.
Adjuvant therapy can include one of several approaches involving chemotherapy and radiation. In general, these approaches include:
(1) Concurrent chemoradiotherapy
(2) Chemotherapy, followed by concurrent chemoradiotherapy
(3) Chemotherapy, followed by concurrent chemoradiotherapy, followed by additional chemotherapy
(4) Chemotherapy alone
(5) Radiotherapy alone (when patient unable to tolerate systemic therapy)
To determine the appropriate adjuvant approach, weigh the risks of locoregional versus distant disease recurrence.
Patients with a high likelihood of distant recurrence: extensive or second echelon nodal disease, baseline CA 19–9 > 100 U/mL, imaging findings suspicious but not conclusive for distant metastases
Patients with a high likelihood of locoregional recurrence: T3/T4 tumors, biliary obstruction or other local disease symptoms at presentation, incomplete or margin-positive resection, lymphovascular invasion/perineural invasion
For most patients, consider initial course of systemic therapy, followed by chemoradiotherapy if patient does not develop distant metastasis.
For patients at high-risk for locoregional recurrence, consider upfront chemoradiotherapy.
Imaging finding of an unresectable, nonmetastatic gallbladder cancer or extrahepatic cholangiocarcinoma; unresectable due to second echelon nodal involvement or extensive primary tumor invasion (e.g., vascular invasion)
Obtain CT or MRI of the abdomen for local staging.
CT chest to assess for distant metastatic disease.
Baseline CA 19–9, CEA.
If elevated bilirubin or jaundiced, evaluate for biliary drainage prior to therapy.
Assess tolerance for systemic therapy.
Proceed with systemic therapy with or without radiotherapy.
Consider upfront chemoradiotherapy in patients with locally symptomatic or T3/T4 disease.
In patients with greater concern for metastatic dissemination, consider upfront chemotherapy followed by chemoradiotherapy if there is no evidence of distant metastasis.
Metastatic disease
Clinical trial enrollment where possible.
Proceed with systemic therapy.
Consider local therapies, including radiation, biliary stenting, and biliary drainage for palliation.
Multidisciplinary supportive and palliative care.
Systemic therapy choices
Chemotherapy alone for metastatic or unresectable disease:
Gemcitabine and cisplatin
Alternative chemotherapy alone options:
Gemcitabine and oxaliplatin (patients unable to tolerate cisplatin)
Gemcitabine alone (elderly patients or patients with comorbidities)
Clinical trial
Chemotherapy alone in the adjuvant setting:
Gemcitabine and capecitabine
Gemcitabine and cisplatin (investigational)
Chemotherapy concurrent with radiotherapy:
CapecitabineRelated posts:
Basics of Chemotherapy
Primary Liver Cancer: Background and Clinical Evidence
Stereotactic Body Radiation Therapy for Liver Metastases: Radiation Therapy Planning
Pancreatic Cancer: Background and Clinical Evidence
Rectal and Colon Cancer: Radiation Therapy Planning
Gastric Cancer: Radiation Therapy Planning
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