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

Abstract

Purpose The vasopressin analog desmopressin (dDAVP) is known to increase plasma levels of hemostatic factors, and preclinical studies in colorectal cancer models have demonstrated that it hampers tumor vascularization and metastatic progression. We evaluated safety and preliminary efficacy of dDAVP in rectal cancer patients with bleeding, before receiving specific oncologic treatment with surgery, chemotherapy and/or radiotherapy. Methods Patients with rectal cancer having moderate or severe rectal bleeding were enrolled in an open-label, dose-finding trial. Intravenous infusions of dDAVP were administered during two consecutive days in doses from 0.25 to 2.0 µg/kg, using single or twice daily regimen. Bleeding was graded using a score based on the Chutkan scale and tumor perfusion was evaluated by dynamic contrast-enhanced magnetic resonance imaging. Results The trial accrued a total of 32 patients. Dose-limiting toxicity occurred in patients receiving 1 µg/kg or higher. The most prominent treatment-related severe adverse event was hyponatremia. Most patients receiving the maximum tolerated dose of 0.5 µg/kg showed at least a partial hemostatic response and 58% developed a complete response with absence of bleeding at day 4 and/or at the last follow-up at day 14. Tumor perfusion was decreased in two-thirds of patients after dDAVP treatment. Conclusions dDAVP appeared as a promising hemostatic agent in rectal cancer patients with bleeding. Randomized clinical trials to confirm its effectiveness are warranted. Clinical trial registration www.clinicaltrials.gov NCT01623206

Potential clinical applications of current and future oral forms of desmopressin (Review)

“…In animal studies, infusion of desmopressin during surgery appears to inhibit perioperative metastatic events and may impede micro-metastases that occurred before surgery (109,111). However, high doses of desmopressin have been used in human trials of desmopressin for cancer treatment: two 1 µg/kg intravenous doses (one just before surgery, one 24 h after surgery) in one study (109) and a maximum tolerated dose of 2x0.5 µg/kg/12 h in another (110).…”

Vasopressin and Its Analogues: From Natural Hormones to Multitasking Peptides

“…After one month, the level of cytokeratin-19 transcript returned to the baseline detected before surgery. The next phase I/II trial (NCT01623206) demonstrated that dDAVP may be considered as a promising hemostatic agent in rectal cancer patients with bleeding [ 186 ]. After a short, two-day treatment with dDAVP most patients showed at least a partial hemostatic response while about 60% had complete absence of bleeding symptoms at fourth day after the treatment started.…”

Anticancer activity of repurposed hemostatic agent desmopressin on AVPR2‑expressing human osteosarcoma

“…A clinically validated dDAVP dose of 1 µg/kg i.v. was taken as the reference dose (15,(30)(31)(32) and multiplied by 12.3 for human to mice conversion (33). Mice equivalent dose was rounded down from 12.3 to 12 µg/kg i.v.…”

“…In a second phase I/II clinical trial, safety and symptom control were assessed in rectal cancer patients with bleeding. As a result, after 4 days of treatment initiation, complete hemostatic control and reduction of tumor vascular perfusion were achieved in the vast majority of patients ( 32 ). Despite dDAVP deployed interesting and promising anticancer activity as a repurposed agent in a variety of experimental and clinical settings, its potential therapeutic benefits in osteosarcoma were never evaluated.…”