Hypercalcemia in Patients With Cholangiocarcinoma

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In a study reported in a research letter in JAMA Oncology, Konstantinidou et al found that the prevalence of hypercalcemia increased over time in patients with cholangiocarcinoma and was significantly more common in those with IDH1-mutant intrahepatic disease.

Study Details

The study involved patients identified from an institutional tumor registry and biobanking database (Beth Israel Deaconess Medical Center and Mass General Cancer Center) who were diagnosed with intrahepatic or extrahepatic cholangiocarcinoma between June 2009 and September 2019. Hypercalcemia was defined as one or more documented albumin-corrected calcium values greater than 10.5 mg/dL.

Key Findings

The prevalence of hypercalcemia at diagnosis (n = 362) was 11%. Among 261 patients with additional measurements, the prevalence increased to 31% in assessments any time during disease course, including 67 (37%) of 182 patients with intrahepatic vs 13 (16%) of 79 with extrahepatic cholangiocarcinoma (P = .001).

A total of 29% of patients with hypercalcemia had IDH1-mutant disease, compared with 10% of those with normocalcemia (P = .008). Among patients with IDH1-mutant vs IDH1 wild-type disease, hypercalcemia occurred in 60% vs 29% (P = .008). Hypercalcemia was associated with high tumor burden in intrahepatic disease and poor tumor differentiation in extrahepatic disease.

A total of 44% of patients with hypercalcemia based on corrected calcium had normal uncorrected calcium levels. Hypercalcemia was documented less frequently in clinician notes in patients with normal vs high uncorrected calcium levels (20% vs 62%, P = .002). Bisphosphonates were used less frequently when hypercalcemia was not documented (0% vs 68%, P < .001).

Median overall survival from the first hypercalcemia event was 4.9 months among patients with intrahepatic disease and 1.8 months in those with extrahepatic disease, suggesting an association with poor prognosis. Among all patients with IDH1-mutant intrahepatic disease, median overall survival was 13.9 months among those with hypercalcemia vs 23.7 months among those with normocalcemia (P = .04). 

The investigators stated, “Findings highlight the high rate of hypercalcemia in patients with advanced cholangiocarcinoma, with the 37% rate in intrahepatic [disease] surpassing rates reported in other tumor types known to have high rates of this metabolic complication. IDH1-mutant intrahepatic [disease] was associated with hypercalcemia. To our knowledge, this represents the first study to identify an association between hypercalcemia and a therapeutically relevant oncogenic mutation. Understanding potential mechanisms warrants further study, including if similar associations exist across other IDH1-mutant tumors. Collectively, findings support the importance of molecular profiling in cholangiocarcinoma, particularly in patients with hypercalcemia, to assess suitability for treatment with an IDH1 inhibitor.”

Lipika Goyal, MD, MPhil, of Stanford Cancer Institute, is the corresponding author for the JAMA Oncology article.

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