Perioperative administration of desmopressin (dDAVP) in breast cancer patients: A phase II dose-escalation study

WEINBERG RUTH; GRECCO MARCELO; FERRO GIMENA ; PERRONI NANCY; TERRIER FRANCISCO; SEIGELSHIFER DEBORA; SANCHEZ LUCEROS ANALIA; DOMENICHINI ENZO; GUTHMANN MARCELO D; DI LEO DANIELA; SPITZER EDUARDO; CICCIA GRACIELA; TORBIDONI ANA VANESA; GARONA JUAN; PIFANO MARINA; RIPOLL GISELLE; GOMEZ ROBERTO ; ALONSO DANIEL

Simposio; San Antonio Breast Cancer Symposium; 2014

Background: dDAVP is a well known peptide analog of the antidiuretic hormone vasopressin, that has been used toprevent bleeding during surgical procedures in patients with hemostatic disorders. It induces a rapid increase of hemostaticmediators by stimulating their release from microvascular endothelial cells. In preclinical studies, dDAVP inhibited lymph nodeand early blood-borne metastasis from aggressive mouse mammary tumors. Besides, perioperative administration of dDAVPsignificantly prolonged disease-free and overall survival in a veterinary clinical trial enrolling dogs with locally advanced mammarycancer. 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 releaseof von Willebrand factor (vWF), which may cause apoptosis of micrometastatic cells. Considering its hemostatic andantimetastatic properties, a phase II dose-escalation trial was performed in patients with breast cancer, administering alyophilized 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 diagnosisof breast carcinoma (Stage 0, I, II), and mastectomy or lumpectomy with sentinel node biopsy, either requiring or not furtheraxillary dissection. dDAVP was administered in two IV infusions, the first 30-60 minutes before surgery and the second 24 hourslater. 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 mg/kg. Primaryendopoints were safety and tolerability in breast cancer patients undergoing surgery as first treatment, as well as selection of thebest 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 thethird dose level (1.25 mg/kg), including nausea, hot flushing, skin rash, dyspnea and palpitations. Reactions were adequatelymanaged by slowing the infusion rate of dDAVP (over 30 minutes). A reduced intraoperative bleeding of up to 50% was notedwith increasing doses of dDAVP. Both vWF antigen and activity showed a rise after each dDAVP infusion, and maximum plasmalevels were obtained at the higher dose level of 2 mg/kg. Interestingly, a preliminary analysis indicated a drop in CTC counts24-48 hours after dDAVP treatment in patients with detectable CK-19 mRNA preoperative levels.Conclusions: At the highest dose level evaluated (2 mg/kg) perioperative dDAVP appeared safe when administered in two slow IVinfusions of 1 mg/kg, before and after the surgical procedure. The available data suggest that treatment is associated withreduction of intraoperative bleeding, higher circulating vWF levels and postoperative drop in CTC counts. Final results will beavailable at the time of the meeting.