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).

Background: dDAVP is a well known peptide analog of the antidiuretic hormone vasopressin, that has been used to prevent bleeding during surgical procedures in patients with hemostatic disorders. It induces a rapid increase of hemostatic mediators by stimulating their release from microvascular endothelial cells. In preclinical studies, dDAVP inhibited lymph node and early blood-borne metastasis from aggressive mouse mammary tumors. Besides, perioperative administration of dDAVP significantly prolonged disease-free and overall survival in a veterinary clinical trial enrolling dogs with locally advanced mammary cancer. The compound is a selective agonist of V2 vasopressin receptors present on both endothelial and breast cancer cells. Recent evidence indicated that dDAVP promotes tumor-mediated production of angiostatin and also activates endothelial release of von Willebrand factor (vWF), which may cause apoptosis of micrometastatic cells. Considering its hemostatic and antimetastatic properties, a phase II dose-escalation trial was performed in patients with breast cancer, administering a lyophilized formulation of dDAVP by IV infusion in saline, before and after surgical resection of primary tumor. Methods: Eligibility included otherwise healthy female patients between 18 and 65 years of age, histological/cytological diagnosis of breast carcinoma (Stage 0, I, II), and mastectomy or lumpectomy with sentinel node biopsy, either requiring or not further axillary dissection. dDAVP was administered in two IV infusions, the first 30-60 minutes before surgery and the second 24 hours later. Five groups of at least 4 patients each received increasing total dDAVP doses of 0.5, 1.0, 1.25, 1.5 and 2.0 μg/kg. Primary endopoints were safety and tolerability in breast cancer patients undergoing surgery as first treatment, as well as selection of the best dose for clinical use. Secondary endpoints included surgical bleeding, plasma levels of vWF, and circulating tumor cells (CTC) as measured by quantitative PCR detection of cytokeratin 19 (CK-19) mRNA in whole blood. Results: The trial accrued 21 patients from April 2012 to February 2014. Adverse events were reversible and observed from the third dose level (1.25 μg/kg), including nausea, hot flushing, skin rash, dyspnea and palpitations. Reactions were adequately managed by slowing the infusion rate of dDAVP (over 30 minutes). A reduced intraoperative bleeding of up to 50% was noted with increasing doses of dDAVP. Both vWF antigen and activity showed a rise after each dDAVP infusion, and maximum plasma levels were obtained at the higher dose level of 2 μg/kg. Interestingly, a preliminary analysis indicated a drop in CTC counts 24-48 hours after dDAVP treatment in patients with detectable CK-19 mRNA preoperative levels. Conclusions: At the highest dose level evaluated (2 μg/kg) perioperative dDAVP appeared safe when administered in two slow IV infusions of 1 μg/kg, before and after the surgical procedure. The available data suggest that treatment is associated with reduction of intraoperative bleeding, higher circulating vWF levels and postoperative drop in CTC counts. Final results will be available at the time of the meeting. Clinical trial number: NCT01606072. Citation Format: Ruth S Weinberg, Marcelo O Grecco, Gimena S Ferro, Debora Seigelshifer, Nancy V Perroni, Francisco J Terrier, Analia Sanchez Luceros, Enzo Domenichini, Marcelo D Guthmann, Daniela Di Leo, Eduardo Spitzer, Graciela N Ciccia, Ana V Torbidoni, Juan Garona, Marina Pifano, Giselle V Ripoll, Roberto E Gomez, Daniel F Alonso. Perioperative administration of desmopressin (dDAVP) in breast cancer patients: A phase II dose-escalation study [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-11-07.