Targeted Therapy for Resistant Cholangiocarcinoma with Bevacizumab or Cetuximab Added to Failed Cytotoxic Drug Cores

Abstract

Background: Addition of bevacizumab/targeted therapy to cores consisting of four to five previously failed cytotoxic drugs employed at low/moderate dosages has produced third- and fourth-line regression of refractory gastric and ovarian cancer. Targeted therapy added to cores of previously failed drugs has similarly produced responses of refractory pancreatic cancer.

Patients and methods: The aim of the present study was to evaluate the addition of targeted therapy to failed cores for patients with end-stage disease. Patients all had end-stage measurable cholangiocarcinoma and active progression during treatment with cores. Targeted therapy, bevacizumab or cetuximab, at standard dosages and schedule was added to the failed cores, which consisted of: gemcitabine, fluorouracil, leucovorin and irinotecan on day 1, and a platin with/without docetaxel on day 2, each at its prior dose and schedule. Electronic medical records facilitated identification of patients for intent-to-treat analysis.

Results: All 13 patients had measurable disease; all standard cytotoxins had been used and failed before the start of treatment with targeted therapy added to the cores. The response rates according to the Response Evaluation Criteria in Solid Tumors and response duration range were: bevacizumab cores: 3/6, 6 to 19 months, and cetuximab cores: 5/7, 10 to 28 months. Responses produced clinical benefit and one late neoadjuvant R0 resection. There were no limiting hematological adverse events due to the cores. Limiting adverse events were hypertension in two patients and an easily controlled duodenal ulcer in one.

Conclusion: Bevacizumab cores and cetuximab cores both produced response rates which satisfy phase II criteria for further investigation. As cores, failed cytotoxic drugs, many at one-quarter to half of their standard doses have been found to produce synergistic benefit in combination with targeted therapy for end-stage patients in four diseases. Co-treatment with no longer active cytotoxic core drugs can demonstrate efficacy attributable to the targeted therapy. This approach is a worthy, cost-effective fast-track registration strategy and distinctly different from trials testing primary treatment.

Keywords: Bevacizumab; cetuximab; cholangiocarcinoma; drug resistance; low-dose cytotoxins.