Phase II Trial of Trifluridine/Tipiracil Plus Irinotecan in Patients with Advanced, Refractory Biliary Tract Carcinoma.

BACKGROUND: We sought to determine the safety and efficacy of trifluridine/tipiracil in combination with irinotecan in a phase II trial setting for refractory, advanced unresectable biliary tract carcinoma (BTC). METHODS: A total of 28 patients (27 were evaluable) with advanced BTCs who progressed on at least one prior systemic therapy were enrolled and were treated with trifluridine/tipiracil 25 mg/m2 (days 1-5 of 14-day cycle) and irinotecan 180 mg/m2 (day 1 of the 14-day cycle). The primary endpoint for the study was 16-week progression-free survival (PFS16) rate. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and safety were pre-specified secondary endpoints. RESULTS: Of 27 patients, PFS16 rate was 37% (10/27; 95% CI: 19%-58%), thereby meeting the criteria for success for the primary endpoint. The median PFS and OS of the entire cohort were 3.9 months (95% CI: 2.5-7.4) and 9.1 months (95% CI: 8.0-14.3), respectively. In the patients evaluable for tumor response (n = 20), the ORR and DCR were 10% and 50%, respectively. Twenty patients (74.1%) had at least one grade 3 or worse adverse event (AE), and 4 patients (14.8%) had grade 4 AEs. A total of 37% (n = 10/27) and 51.9% (n = 14/27) experienced dose reductions in trifluridine/tipiracil and irinotecan, respectively. Delay in therapy was noted in 56% of the patients while 1 patient discontinued the therapy, primarily due to hematologic AEs. CONCLUSION: The combination of trifluridine/tipiracil plus irinotecan is a potential treatment option for patients with advanced, refractory BTCs with good functional status and no targetable mutations. A larger randomized trial is needed to confirm these results. (ClinicalTrials.gov Identifier: NCT04072445).

Phase II Trial of Trifluridine/Tipiracil in Patients with Advanced, Refractory Biliary Tract Carcinoma.

LESSONS LEARNED: Trifluridine/tipiracil (FTD/TPI) shows promising antitumor activity in heavily pretreated patients with advanced biliary tract carcinoma, including patients with 5-fluorouracil refractory tumors. FTD/TPI has an acceptable safety profile and should be studied further in patients with advanced biliary tract carcinoma after progression on standard first-line therapy. BACKGROUND: Patients with advanced biliary tract carcinoma (BTC) refractory to first-line therapy lack an established second-line option. Trifluridine/tipiracil (FTD/TPI) has activity in both fluoropyrimidine-sensitive and -resistant tumors, which led us to conduct a single arm phase II trial to evaluate the safety and efficacy of FTD/TPI for patients previously treated for advanced BTC. METHODS: Patients with advanced BTC previously treated with at least one line of chemotherapy were enrolled and treated with FTD/TPI until disease progression or unacceptable toxicity. The primary endpoint target was to have at least 6 patients who were progression free and alive at 16 weeks among 25 evaluable patients. Secondary endpoints included overall survival (OS), overall response rate (ORR), progression-free survival (PFS), and toxicity. RESULTS: Of 27 evaluable patients, 59.3% received at least three prior lines of therapy, and 81.5% had previous exposure to fluoropyrimidine. Eight (32%, 95% confidence interval [CI], 14.9%-53.5%) patients were progression free at 16 weeks in the primary analysis population (n = 25), which met the predefined efficacy criteria. Median PFS and OS were 3.8 (95% CI, 2-5.8 months) and 6.1 (95% CI, 4.4-11.4 months) months, respectively. No objective responses were seen. There were no unexpected safety signals noted. CONCLUSION: FTD/TPI demonstrated promising antitumor activity, with acceptable toxicity, in heavily pretreated patients with advanced BTC.

Bolus 5-fluorouracil (5-FU) In Combination With Oxaliplatin Is Safe and Well Tolerated in Patients Who Experienced Coronary Vasospasm With Infusional 5-FU or Capecitabine.

INTRODUCTION: Coronary vasospasm associated with fluoropyrimidine (FP)-based chemotherapy is a potentially serious complication and reported to occur more often with infusional 5-fluorouracil (5-FU) or capecitabine than with bolus 5-FU. Given the additional benefit of oxaliplatin over FP alone in the management of colorectal cancer, retaining oxaliplatin in the treatment regimen is desirable, but the safety of combining bolus 5-FU with oxaliplatin in patients with FP-induced vasospasm is not well established. We performed a retrospective review to explore the safety of substituting FLOX (bolus 5-FU, oxaliplatin, leucovorin) for FOLFOX (infusional 5-FU, oxaliplatin, leucovorin) and CAPOX (capecitabine, oxaliplatin) in patients who had FP-induced coronary vasospasm. PATIENTS AND METHODS: The pharmacy database of Mayo Clinic was queried to identify patients who developed coronary vasospasm associated with FOLFOX or CAPOX between January 2011 and January 2018 and were subsequently treated with FLOX. Detailed information was obtained on these patients by retrospective electronic chart review. RESULTS: A total of 10 patients (median age, 56.5 years; range, 36-77 years) were identified, 9 with FOLFOX and 1 with CAPOX. Among the patients treated with FOLFOX, 8 patients had chest pain as the presenting complaint that had started within 48 hours of beginning of the 5-FU infusion. In 9 of 10 patients, coronary vasospasm occurred with the first cycle of therapy. All patients made full recovery after discontinuation of infusional 5-FU or capecitabine. All patients subsequently received FLOX with 7 median bolus 5-FU doses (range, 2-22 doses) and 7 median oxaliplatin doses (range, 2-12 doses) at 7 days to 18 months after the event, with 7 patients treated within 4 weeks of the event. FLOX did not cause any cardiovascular adverse events in any of the 10 patients. CONCLUSION: Bolus 5-FU in combination with oxaliplatin is safe in patients who have experienced coronary vasospasm with infusional 5-FU or capecitabine.

Prognostic factors and benefits of adjuvant therapy after pancreatoduodenectomy for ampullary adenocarcinoma: Mayo Clinic experience.

INTRODUCTION: Ampullary adenocarcinoma is a rare entity with limited data on prognostic factors. The aim of this study is to identify prognostic factors and assess the benefit of adjuvant therapy in patients with ampullary adenocarcinoma who underwent pancreatoduodenectomy. METHODS: A cohort of 121 consecutive patients underwent pancreatoduodenectomy for ampullary adenocarcinoma from 2006 to 2016 at Mayo Clinic in Rochester, MN. All patients were confirmed by independent pathologic review to have ampullary carcinoma. Patient survival and its correlation with patient and tumor variables were evaluated by univariate and multivariate analysis. RESULTS: Fifty three patients (45%) received adjuvant therapy (34 patients had chemotherapy alone, while 19 patients received both chemotherapy and radiation therapy). Fifty seven percent of the patients were diagnosed with advanced stage disease (Stage IIB or higher). Nearly all patients (98.3%) had negative surgical margins. Median overall survival (OS) was 91.8 months (95% CI:52.6 months-not reached). In multivariate analysis, excellent performance status (ECOG: 0), adjuvant therapy, and advanced stage remained statistically significant. Adjuvant therapy was independently associated with improved disease free survival (Hazard ratio [HR]:0.52, P = 0.04) and overall survival (HR:0.45, P = 0.03) in patients with advanced disease. CONCLUSIONS: Adjuvant therapy was associated with improved survival in patients with resected ampullary cancer, especially with advanced stage disease. A multi-institutional randomized trial is needed to further assess the role of adjuvant therapy in ampullary adenocarcinoma.

Malignant transformation of biliary adenofibroma: a rare biliary cystic tumor.

Biliary adenofibromas (BAFs) are rare, benign biliary cystic tumors with potential for malignant transformation. Of the eleven prior cases of BAF reported in the literature, six showed evidence of malignant transformation. We describe the clinical, imaging and pathology features of two cases of malignant BAF and review the existing literature to raise awareness of this entity and provide additional tools for diagnosing this rare tumor Additionally, we identified a loss of function mutation in the cyclin-dependent kinase inhibitor 2A (CDKN2A) tumor suppressor gene in a malignant caudate lobe BAF, thereby providing potential insight into the molecular pathogenesis of BAF malignant transformation. Although additional cases and longer-term follow-up are needed, our cases suggest that recurrence or metastasis of malignant BAF is not common and that complete surgical resection can be curative.

Capecitabine and temozolomide: design, implementation, and preliminary outcomes from a pilot project to ensure safe prescribing of oral chemotherapy.

Without adequate safety measures, oral chemotherapy can lead to undetected dosing errors. The Mayo Clinic launched a project to ensure that all capecitabine and temozolomide prescriptions receive an independent double check.

E-mail and photographs: a case report of a patient-initiated diagnostic tool in the era of electronic communication.

This case report reviews some of the clinical aspects of epidermal growth factor receptor (EGFR) inhibitor-induced rash, and, more importantly, it describes a specific case in which the diagnosis of such a rash occurred by means of a patient-initiated photographic electronic communication. The fact that this electronic communication was patient-initiated suggests that health care providers will likely be asked to make clinical decisions based on this type of communication soon and that this type of seemingly low-cost approach will likely become an important aspect of cancer symptom control and palliative care in the future.

Importance of device evaluation for point-of-care prothrombin time international normalized ratio testing programs.

OBJECTIVE: To determine the accuracy of 2 commercially available point-of-care devices relative to plasma international normalized ratio (INR) values. PATIENTS AND METHODS: Point-of-care INR testing was performed with the CoaguChek and ProTime 3 devices in consecutive patients attending an anticoagulation clinic between June 18, 2003, and August 6, 2003. Results were compared with plasma INRs using a sensitive thromboplastin (International Sensitivity Index, 1.0). RESULTS: Ninety-four patients agreed to participate in the study. Relative to the plasma INR, values were in agreement +/-0.4 INR unit 82% and 39% of the time for the CoaguChek and ProTime 3 devices, respectively. The mean +/- SD CoaguChek INRs were 0.2+/-0.31 unit lower, whereas ProTime 3 INRs were 0.8+/-0.68 unit higher than plasma INR values. Treatment decisions based on these data would have resulted in inappropriate dose adjustments 10% and 22% of the time for these 2 respective devices. Correlation with plasma was greater for the CoaguChek (r2=0.90) compared with the ProTime 3 device (r2=0.73). CONCLUSIONS: Optimal warfarin treatment requires accurate measurement of the INR. The choice of a point-of-care device for INR management depends on the reliability of INR data generated by the device.