A phase II dose-escalation trial of perioperative desmopressin (1-desamino-8-d-arginine vasopressin) in breast cancer patients

Abstract

Desmopressin (dDAVP) is a well-known peptide analog of the antidiuretic hormone vasopressin, used to prevent excessive bleeding during surgical procedures. dDAVP increases hemostatic mediators, such as the von Willebrand factor (vWF), recently considered a key element in resistance to metastasis. Studies in mouse models and veterinary trials in dogs with locally-advanced mammary tumors demonstrated that high doses of perioperative dDAVP inhibited lymph node and early blood-borne metastasis and significantly prolonged survival. We conducted a phase II dose-escalation trial in patients with breast cancer, administering a lyophilized formulation of dDAVP by intravenous infusion in saline, 30–60 min before and 24 h after surgical resection. Primary endpoints were safety and tolerability, as well as selection of the best dose for cancer surgery. Secondary endpoints included surgical bleeding, plasma levels of vWF, and circulating tumor cells (CTCs) as measured by quantitative PCR of cytokeratin-19 transcripts. Only 2 of a total of 20 patients experienced reversible adverse events, including hyponatremia (grade 4) and hypersensitivity reaction (grade 2). Reactions were adequately managed by slowing the infusion rate. A reduced intraoperative bleeding was noted with increasing doses of dDAVP. Treatment was associated with higher vWF plasma levels and a postoperative drop in CTC counts. At the highest dose level evaluated (2 μg/kg) dDAVP appeared safe when administered in two slow infusions of 1 μg/kg, before and after surgery. Clinical trials to establish the effectiveness of adjunctive perioperative dDAVP therapy are warranted. This trial is registered on www.clinicaltrials.gov (NCT01606072).

Selective Inhibition of ADAM28 Suppresses Lung Carcinoma Cell Growth and Metastasis

“…Intriguingly, the antibody treatment cured metastasis in 30% of the experimental mice, enabling them to accomplish their life free from cancer cells. Recent report on a phase II dose-escalation trial of desmopressin in breast cancer patients has demonstrated that administration of desmopressin, which stimulates the release of VWF from endothelial cells (31), reduces circulating cancer cells by increasing blood levels of VWF (32). Altogether, it is plausible to think that our antibody is useful for prevention of micrometastases by extinguishing circulating cancer cells, which are commonly detected in cancer patients, including NSCLC patients (33).…”

Antiproliferative Effects of Oxytocin and Desmopressin on Canine Mammary Cancer Cells

“…More recently, a phase II dose-escalation trial in women with breast cancer was performed, demonstrating that DDAVP, administered 30–60 min before and 24 h after surgical resection, reduced intraoperative bleeding and the number of circulating tumor cells. Moreover, it appeared to be safe and well tolerated at the highest dose level evaluated (2 µg/kg) (37). …”

Administration of the vasopressin analog desmopressin for the management of bleeding in rectal cancer patients: results of a phase I/II trial

“…A recent clinical trial in breast cancer patients administered with perioperative infusions of dDAVP demonstrated a reduced intrasurgical bleeding with increasing doses of the compound. Interestingly, treatment was associated with higher VWF plasma levels and a postoperative decrease in circulating tumor cell counts [14].…”