Capecitabine and fluorouracil dosing

The DPYD gene encodes an enzyme that catabolizes pyrimidines and fluoropyrimidines, like capecitabine and fluorouracil. An estimated 1% to 2% of the population has germline pathogenic variants in DPYD, which lead to reduced DPD protein function and an accumulation of pyrimidines and fluoropyrimidines in the body.[2,3] Patients with the DPYD*2A variant who receive fluoropyrimidines may experience severe, life-threatening toxicities that are sometimes fatal. Many other DPYD variants have been identified, with a range of clinical effects.[2-4] Fluoropyrimidine avoidance or a dose reduction of 50% may be recommended based on the patient's DPYD genotype and number of functioning DPYD alleles.[5-7] DPYD genetic testing costs less than $200, but insurance coverage varies due to a lack of national guidelines.[8] In addition, testing may delay therapy by 2 weeks, which would not be advisable in urgent situations. This controversial issue requires further evaluation.[9]

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Evidence (systemic therapy):

In a phase III study, 410 patients with unresectable metastatic, or recurrent biliary tract cancer were randomly assigned to receive up to 6 months of gemcitabine with or without cisplatin.[10]

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In a phase III study, 410 patients with unresectable metastatic, or recurrent biliary tract cancer were randomly assigned to receive up to 6 months of gemcitabine with or without cisplatin.[10]

With a median follow-up of 8.2 months, the median overall survival (OS) was superior for patients who received combination chemotherapy (11.7 months vs. 8.1 months; hazard ratio [HR], 0.64; 95% confidence interval [CI], 0.52–0.80; P < .001).[10][Level of evidence A1]

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In a phase III study, 410 patients with unresectable metastatic, or recurrent biliary tract cancer were randomly assigned to receive up to 6 months of gemcitabine with or without cisplatin.[10]

A similar median OS benefit was demonstrated in all subgroups, including 149 patients with gallbladder cancer.

In a phase III study, 410 patients with unresectable metastatic, or recurrent biliary tract cancer were randomly assigned to receive up to 6 months of gemcitabine with or without cisplatin.[10]

Grade 3 and 4 toxicities occurred with similar frequency in both study arms, except for increased hematologic toxic effects in patients who received gemcitabine plus cisplatin and increased hepatotoxicity in patients who received single-agent gemcitabine.

An international, multicenter, phase III study (TOPAZ-1 [NCT03875235]) included 685 patients with previously untreated and unresectable locally advanced, recurrent, or metastatic biliary tract cancer. Patients were randomly assigned to receive either durvalumab or placebo with cisplatin plus gemcitabine for up to eight cycles, followed by durvalumab or placebo maintenance until disease progression or unacceptable toxicity. After a median follow-up of 23.4 months for patients in the durvalumab group, the following was observed:[11,12]

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An international, multicenter, phase III study (TOPAZ-1 [NCT03875235]) included 685 patients with previously untreated and unresectable locally advanced, recurrent, or metastatic biliary tract cancer. Patients were randomly assigned to receive either durvalumab or placebo with cisplatin plus gemcitabine for up to eight cycles, followed by durvalumab or placebo maintenance until disease progression or unacceptable toxicity. After a median follow-up of 23.4 months for patients in the durvalumab group, the following was observed:[11,12]

The primary end point of median OS was 12.9 months in the durvalumab group and 11.3 months in the placebo group (HR, 0.76; 95% CI, 0.64–0.91). In the durvalumab group, the 18-month OS rate was 35.1%, and the 24-month OS was 24.9%. In the placebo group, the 18-month OS rate was 25.5%, and the 24-month OS rate was 10.4%.[11,12][Level of evidence A1]

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An international, multicenter, phase III study (TOPAZ-1 [NCT03875235]) included 685 patients with previously untreated and unresectable locally advanced, recurrent, or metastatic biliary tract cancer. Patients were randomly assigned to receive either durvalumab or placebo with cisplatin plus gemcitabine for up to eight cycles, followed by durvalumab or placebo maintenance until disease progression or unacceptable toxicity. After a median follow-up of 23.4 months for patients in the durvalumab group, the following was observed:[11,12]

There was no significant difference between groups in the number of grade 3 or 4 treatment-related adverse events or the number of events leading to discontinuation of a study medication.

An international, multicenter, phase III study (KEYNOTE-966 [NCT04003636]) enrolled 1,069 patients with previously untreated unresectable, locally advanced or metastatic biliary tract cancer. Patients were randomly assigned to receive either pembrolizumab or placebo for up to 35 cycles. This was combined with gemcitabine (with no maximum duration) and cisplatin for up to 8 cycles. After a median follow-up of 25.6 months, the following results were observed:[13][Level of evidence A1]

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An international, multicenter, phase III study (KEYNOTE-966 [NCT04003636]) enrolled 1,069 patients with previously untreated unresectable, locally advanced or metastatic biliary tract cancer. Patients were randomly assigned to receive either pembrolizumab or placebo for up to 35 cycles. This was combined with gemcitabine (with no maximum duration) and cisplatin for up to 8 cycles. After a median follow-up of 25.6 months, the following results were observed:[13][Level of evidence A1]

The median OS was 12.7 months in the pembrolizumab group and 10.9 months in the placebo group (HR, 0.83; 95% CI, 0.72–0.95; one-sided P = .0034).

An international, multicenter, phase III study (KEYNOTE-966 [NCT04003636]) enrolled 1,069 patients with previously untreated unresectable, locally advanced or metastatic biliary tract cancer. Patients were randomly assigned to receive either pembrolizumab or placebo for up to 35 cycles. This was combined with gemcitabine (with no maximum duration) and cisplatin for up to 8 cycles. After a median follow-up of 25.6 months, the following results were observed:[13][Level of evidence A1]

There was no difference in the total frequency of treatment-related adverse events between treatment groups, including grade 3 or grade 4 events. Death due to treatment-related adverse events was seen in a total of eight patients (2%) in the pembrolizumab arm and three patients (1%) in the placebo arm.

A three-arm randomized phase III study of patients with unresectable gallbladder cancer compared best supportive care (n = 27), fluorouracil plus folinic acid (FUFA) weekly for 30 weeks (n = 28), and modified gemcitabine plus oxaliplatin (mGEMOX) for up to six 21-day cycles.[14][Level of evidence A1]

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A three-arm randomized phase III study of patients with unresectable gallbladder cancer compared best supportive care (n = 27), fluorouracil plus folinic acid (FUFA) weekly for 30 weeks (n = 28), and modified gemcitabine plus oxaliplatin (mGEMOX) for up to six 21-day cycles.[14][Level of evidence A1]

With a median follow-up of 9 months, the OS was 4.5 months for patients who received best supportive care (95% CI, 0.2−8.8), 4.6 months for patients who received FUFA (95% CI, 3−6.2), and 9.5 months for patients who received mGEMOX (95% CI, 5−14; P = .039).

A three-arm randomized phase III study of patients with unresectable gallbladder cancer compared best supportive care (n = 27), fluorouracil plus folinic acid (FUFA) weekly for 30 weeks (n = 28), and modified gemcitabine plus oxaliplatin (mGEMOX) for up to six 21-day cycles.[14][Level of evidence A1]

The only significant difference in grade 3 or 4 toxicities between the chemotherapy arms was transaminitis, which was more prevalent in the mGEMOX arm (P = .04).

A phase III noninferiority study (NCT01470443) enrolled 114 patients with metastatic biliary tract cancers, including 30 (26%) with primary gallbladder cancer. Patients were randomly assigned to receive either capecitabine plus oxaliplatin (XELOX) or gemcitabine plus oxaliplatin (GEMOX).[15][Level of evidence B1]

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A phase III noninferiority study (NCT01470443) enrolled 114 patients with metastatic biliary tract cancers, including 30 (26%) with primary gallbladder cancer. Patients were randomly assigned to receive either capecitabine plus oxaliplatin (XELOX) or gemcitabine plus oxaliplatin (GEMOX).[15][Level of evidence B1]

OS was not significantly different, at 10.4 months (95% CI, 8.0−12.6) for patients in the GEMOX group and 10.6 months (95% CI, 7.3−15.5) for patients in the XELOX group (P = .131).

A phase III noninferiority study (NCT01470443) enrolled 114 patients with metastatic biliary tract cancers, including 30 (26%) with primary gallbladder cancer. Patients were randomly assigned to receive either capecitabine plus oxaliplatin (XELOX) or gemcitabine plus oxaliplatin (GEMOX).[15][Level of evidence B1]

The primary end point of 6-month progression-free survival (PFS) rates were 44.6% for the GEMOX group and 46.7% for the XELOX group (95% CI of difference in 6-month PFS rate, -12% to 16%, meeting criteria for noninferiority).

A phase III noninferiority study (NCT01470443) enrolled 114 patients with metastatic biliary tract cancers, including 30 (26%) with primary gallbladder cancer. Patients were randomly assigned to receive either capecitabine plus oxaliplatin (XELOX) or gemcitabine plus oxaliplatin (GEMOX).[15][Level of evidence B1]

A predefined subgroup analysis based on the primary site of disease was performed. The analysis did not reveal a difference in objective response rate between the two arms in patients with gallbladder cancer (P = .598).

Pending additional clinical trials, cisplatin plus gemcitabine is considered the reference standard chemotherapy backbone for patients with unresectable, metastatic, or recurrent gallbladder cancer. Extrapolating from the results of the TOPAZ-1 and KEYNOTE-966 trials for biliary tract cancer, addition of a checkpoint inhibitor (durvalumab or pembrolizumab) to first-line therapy has become the standard of care. Potential alternative regimens include gemcitabine plus capecitabine, GEMOX, and XELOX. All patients should consider clinical trials.

All patients with unresectable, metastatic, or recurrent disease who have not already received checkpoint inhibitors should undergo molecular testing for deficient mismatch repair (dMMR) or microsatellite instability (MSI-H). Extrapolating from a subgroup of patients with gastrointestinal and hepatopancreatobiliary tumors in the I-PREDICT (NCT02534675) and KEYNOTE-158 (NCT02628067) studies, patients with either dMMR or MSI-H tumors can be considered for treatment with pembrolizumab.[16,17][Level of evidence C3]

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Additional testing for IDH1 variants, FGFR2 gene fusions, and HER2 expression may provide potential targets in clinical trials. In clinical practice, targeted treatments that have been approved by the U.S. Food and Drug Administration as second-line treatments for patients with cholangiocarcinoma could likely be used to treat appropriate patients with gallbladder cancer. Compelling treatment options for these patients are scarce. For more information, see the Targeted therapy section in Bile Duct Cancer (Cholangiocarcinoma) Treatment.

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Targeted therapy

Capecitabine and fluorouracil dosing

Studies cited in this source section

Publication references