The Cholangiocarcinoma in the Young (CITY) Study: Tumor Biology, Treatment Patterns, and Survival Outcomes in Adolescent Young Adults With Cholangiocarcinoma.

PURPOSE: Increased awareness of the distinct tumor biology for adolescents and young adults (AYAs) with cancer has led to improvement in outcomes for this population. However, in cholangiocarcinoma (CCA), a paucity of data exist on the AYA population. To our knowledge, we present the largest study to date on AYA disease biology, treatment patterns, and survival outcomes in CCA. METHODS: A multi-institutional cohort of patients with CCA diagnosed with intrahepatic cholangiocarcinoma (ICC) or extrahepatic cholangiocarcinoma (ECC) was used for analysis. Retrospective chart review was conducted on patients who were 50 years old and younger (young; n = 124) and older than 50 years (older; n = 723). RESULTS: Among 1,039 patients screened, 847 patients met eligibility (72% ICC, 28% ECC). Young patients had a larger median tumor size at resection compared with older patients (4.2 v 3.6 cm; P = .048), more commonly had N1 disease (65% v 43%; P = .040), and were more likely to receive adjuvant therapy (odds ratio, 4.0; 95% CI, 1.64 to 9.74). Tumors of young patients were more likely to harbor an FGFR2 fusion, BRAF mutation, or ATM mutation (P < .05 for each). Young patients were more likely to receive palliative systemic therapy (96% v 69%; P < .001), targeted therapy (23% v 8%; P < .001), and treatment on a clinical trial (31% v 19%; P = .004). Among patients who presented with advanced disease, young patients had a higher median overall survival compared with their older counterparts (17.7 v 13.5 months; 95% CI, 12.6 to 22.6 v 11.4 to 14.8; P = .049). CONCLUSION: Young patients with CCA had more advanced disease at resection, more commonly received both adjuvant and palliative therapies, and demonstrated improved survival compared with older patients. Given the low clinical trial enrollment and poor outcomes among some AYA cancer populations, data to the contrary in CCA are highly encouraging.

Molecular profiling and treatment pattern differences between intrahepatic and extrahepatic cholangiocarcinoma.

BACKGROUND: Treatment patterns for intrahepatic cholangiocarcinoma (ICC) and extrahepatic cholangiocarcinoma (ECC) differ, but limited studies exist comparing them. This study examines differences in molecular profiling rates and treatment patterns in these populations, focusing on use of adjuvant, liver-directed, targeted, and investigational therapies. METHODS: This multicenter collaboration included patients with ICC or ECC treated at 1 of 8 participating institutions. Retrospective data were collected on risk factors, pathology, treatments, and survival. Comparative statistical tests were 2-sided. RESULTS: Among 1039 patients screened, 847 patients met eligibility (ICC = 611, ECC = 236). Patients with ECC were more likely than those with ICC to present with early stage disease (53.8% vs 28.0%), undergo surgical resection (55.1% vs 29.8%), and receive adjuvant chemoradiation (36.5% vs 4.2%) (all P < .00001). However, they were less likely to undergo molecular profiling (50.3% vs 64.3%) or receive liver-directed therapy (17.9% vs 35.7%), targeted therapy (4.7% vs 18.9%), and clinical trial therapy (10.6% vs 24.8%) (all P < .001). In patients with recurrent ECC after surgery, the molecular profiling rate was 64.5%. Patients with advanced ECC had a shorter median overall survival than those with advanced ICC (11.8 vs 15.1 months; P < .001). CONCLUSIONS: Patients with advanced ECC have low rates of molecular profiling, possibly in part because of insufficient tissue. They also have low rates of targeted therapy use and clinical trial enrollment. While these rates are higher in advanced ICC, the prognosis for both subtypes of cholangiocarcinoma remains poor, and a pressing need exists for new effective targeted therapies and broader access to clinical trials.

A phase I pharmacokinetic and safety study of Paclitaxel Injection Concentrate for Nano-dispersion (PICN) alone and in combination with carboplatin in patients with advanced solid malignancies and biliary tract cancers.

PURPOSE: Paclitaxel injection concentrate for nano-dispersion (PICN) is a Cremophor-free, nanotechnology-driven paclitaxel formulation. This phase I study examined the safety, tolerability, pharmacokinetics and maximum tolerated dose (MTD) of PICN alone and in combination with carboplatin. Its early efficacy in unresectable biliary tract cancers (BTCs) was also evaluated. METHODS: This multi-center study comprised two parts. Part A contained a dose-escalation cohort following "3 + 3" design using PICN monotherapy in advanced solid tumors (Part A1); Part A2 dose-expansion cohort was then conducted in advanced BTCs due to observed efficacy in Part A1. Part B1 and B2 evaluated escalating dose of PICN with carboplatin in advanced solid tumors. PICN was administered as a 30 min-infusion every 3 weeks without pre-medications for hypersensitivity reactions. RESULTS: Thirty-six patients received PICN monotherapy in Part A and 21 received PICN plus carboplatin in Part B. The MTD of PICN was determined to be 295 mg/m2 both as a monotherapy and in combination with carboplatin at AUC 5. Dose-proportional exposure in paclitaxel Cmax and AUC was observed overdose range from 175 to 325 mg/m2 for PICN monotherapy and its combination with carboplatin. Carboplatin did not alter PICN exposure. Clinically significant toxicities mainly include neutropenia and peripheral neuropathy. PICN monotherapy yielded a response rate of 20% in unresectable BTCs. CONCLUSION: This study demonstrated the safety and stable pharmacokinetics of PICN as a monotherapy and in combination with carboplatin. Single-agent PICN showed promising antitumor activity in advanced BTCs, warranting further studies to investigate its role in gastrointestinal cancers.

Advances in the management of biliary tract cancers.

Biliary tract cancers, although uncommon, are highly fatal malignancies. Current treatments fail to cure or control the majority of tumors. Given the complexity of the anatomy and the often aggressive nature of the disease, multidisciplinary treatment, including palliation, is often required. However, systemic therapy with cytotoxics and/or targeted agents is routinely the mainstay of treatment for patients with advanced biliary tract cancers, and new targets and agents provide hope for this disease. This article focuses on recent advances in the management of biliary tract cancers, with a special focus on the molecular basis for current therapeutic investigation in this disease.

Safety, pharmacokinetics and pharmacodynamics of the anti-A33 fully-human monoclonal antibody, KRN330, in patients with advanced colorectal cancer.

PURPOSE: The objective of this first-in-human trial included the safety, maximum tolerated dose (MTD), pharmacokinetics, immunogenicity and antitumour effects of KRN330, a novel fully-human monoclonal antibody directed against A33, a membrane bound glycoprotein uniformly expressed in 95% of colorectal cancers. METHODS: Patients with advanced or metastatic colorectal cancer (CRC) refractory to standard therapy were eligible. Twenty-nine patients received weekly intravenous KRN330 (0.1-10mg/kg) for a minimum of 4 weeks in a standard 3+3 design, and nine patients received q2 week doses at 3mg/kg with pre- and post-biopsies to evaluate tumour binding and safety on this schedule. RESULTS: The most common KRN330 related adverse events (all grades) were nausea (66%), diarrhoea (61%) and vomiting (47%). The MTD was 3mg/kg weekly, with dose-limiting grade 3 gastrointestinal toxicities at 10mg/kg and the intermediate dose level of 6 mg/kg. Pharmacokinetics of KRN330 was linear. Stable disease was reported in 12/38 patients (32%), with a median duration of 155 days. There was no evidence of human anti-human antibodies, and immunohistochemistry on biopsy samples demonstrated that KRN330 remained bound to tumour 2 weeks after dosing. CONCLUSIONS: KRN330 is safe and tolerable at the MTD of 3mg/kg once weekly in patients with advanced CRC. Dosing on alternate weeks is supported by tumour binding. The long treatment durations and lack of immunogenicity warrant further investigation of KRN330 in combination.

Advanced biliary tract cancers.

Single-agent management of metastatic biliary tract cancers with 5-fluorouracil (5-FU) or gemcitabine has shown limited efficacy, although 5-FU has been shown to be more effective than best supportive care alone. An analysis of phase II trials has suggested that platinums enhanced the efficacy of single-agent fluoropyrimidines. In a phase III randomized trial comparing single-agent gemcitabine with gemcitabine plus cisplatin, the gemcitabine/cisplatin combination significantly improved median overall survival (OS) and progression-free survival (PFS), which established a new option for standard of care. However, the future of cancer medicine lies in newer, targeted agents. In the management of biliary tract cancers, preliminary evidence with epidermal growth factor receptor inhibitors has already demonstrated activity. This article reviews systemic therapies for metastatic biliary tract cancers as they relate to current and emerging standards of care.