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).

Keywords: Breast cancer trial; Circulating tumor cells; Hemostasia; Surgery; dDAVP; von Willebrand factor.

Fig. 1

Hemostatic effects of perioperative dDAVP. a Number and b weight of surgical pads used during the surgical procedure, as a function of the preoperative first dose of dDAVP (treatment groups 4 and 5 are presented together, since in both cases received 1 µg/kg). *p < 0.05 (1.0 versus 0.25 µg/kg), ANOVA with Tukey post-test. c vWF antigen (vWF:Ag) and d functional vWF (vWF:RCo) levels in samples collected prior to surgery (baseline), and after the preoperative dose (1st dDAVP dose) and the postoperative dose (2nd dDAVP dose). ^#p < 0.05 (2.0 µg/kg versus all other dose levels), two-way ANOVA with Tukey post-test. In all cases, data represent mean ± SEM.

Fig. 2

Detection of circulating tumor cells (CTCs) by qPCR. CTCc were assessed by means of expression of transcripts for CK-19 in whole blood, as described in detail in “Patients and methods”. Samples from 16 patients were obtained within 7 days prior to surgery (baseline), and 24 h, 2 weeks and 1 month after surgery. Data from all treatment groups were pooled. Horizontal lines indicate the median values. The cut-off RQ value was 0.00445 for healthy woman volunteers aged 25–61 years, based on ROC analysis (specificity: 100 %; sensibility: 81.25 %; area = 0.91).

Fig. 3

Immunohistochemical staining of vasopressin receptors. V2R expression was detected using polyclonal antibodies against the human receptor, as described in detail in “Patients and methods”. Representative pictures of tumor sections from patients enrolled in the trial and positive control tissue are depicted. a Breast carcinoma expressing V2R b V2R-negative breast carcinoma c Kidney tubules d MCF-7 human breast carcinoma xenograft. Arrowhead denotes positive staining of small vessels. Original magnification: a, b, d ×400; c ×100.