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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.

SUBMITTER: Iseas S

PROVIDER: S-EPMC7497699 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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

Iseas Soledad S Roca Enrique L EL O'Connor Juan M JM Eleta Martin M Sanchez-Luceros Analia A Di Leo Daniela D Tinelli Marcelo M Fara Maria L ML Spitzer Eduardo E Demarco Ignacio A IA Ripoll Giselle V GV Pifano Marina M Garona Juan J Alonso Daniel F DF

Investigational new drugs 20200312 5

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 rec ...[more]

PMID: 32166534

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Project description:BackgroundTransanal TME (taTME) combines abdominal and transanal dissection to facilitate sphincter preservation in patients with low rectal tumors. Few phase II/III trials report long-term oncologic and functional results. We report early results from a North American prospective multicenter phase II trial of taTME (NCT03144765).Methods100 patients with stage I-III rectal adenocarcinoma located ≤ 10 cm from the anal verge (AV) were enrolled across 11 centers. Primary and secondary endpoints were TME quality, pathologic outcomes, 30-day and 90-day outcomes, and stoma closure rate. Univariable regression analysis was performed to assess risk factors for incomplete TME and anastomotic complications.ResultsBetween September 2017 and April 2022, 70 males and 30 females with median age of 58 (IQR 49-62) years and BMI 27.8 (IQR 23.9-31.8) kg/m2 underwent 2-team taTME for tumors located a median 5.8 (IQR 4.5-7.0) cm from the AV. Neoadjuvant radiotherapy was completed in 69%. Intersphincteric resection was performed in 36% and all patients were diverted. Intraoperative complications occurred in 8% including 3 organ injuries, 2 abdominal and 1 transanal conversion. The 30-day and 90-day morbidity rates were 49% (Clavien-Dindo (CD) ≥ 3 in 28.6%) and 56% (CD ≥ 3 in 30.4% including 1 mortality), respectively. Anastomotic complications were reported in 18% including 10% diagnosed within 30 days. Higher anastomotic risk was noted among males (p = 0.05). At a median follow-up of 5 (IQR 3.1-7.4) months, 98% of stomas were closed. TME grade was complete or near complete in 90%, with positive margins in 2 cases (3%). Risk factors for incomplete TME were ASA ≥ 3 (p = 0.01), increased time between NRT and surgery (p = 0.03), and higher operative blood loss (p = 0.003).ConclusionWhen performed at expert centers, 2-team taTME in patients with low rectal tumors is safe with low conversion rates and high stoma closure rate. Mid-term results will further evaluate oncologic and functional outcomes.

Project description:ObjectiveTo determine whether extending the interval between chemoradiation (CRT) and surgery, and administering additional chemotherapy during the waiting period has an impact on tumor response, CRT-related toxicity and surgical complications in patients with advanced rectal cancer.BackgroundLocally advanced rectal cancer is usually treated with preoperative CRT followed by surgery approximately 6 weeks later. The Timing of Rectal Cancer Response to Chemoradiation Consortium designed a prospective, multicenter, Phase II clinical trial to investigate extending the interval between CRT and surgery, and administering additional chemotherapy during the waiting period. Here, we present preliminary results of this trial, reporting the tumor response, CRT-related toxicity and surgical complications.MethodsStage II and III rectal cancer patients were treated concurrently with 5-Fluorouracil (FU) and radiation for 5 to 6 weeks. Patients in study group (SG) 1 underwent total mesorectal excision (TME) 6 weeks later. Patients in SG2 with evidence of a clinical response 4 weeks after CRT received 2 cycles of modified FOLFOX-6 (mFOLFOX-6) followed by TME 3 to 5 weeks later. Tumor response, CRT-related toxicity and surgical complications were recorded.ResultsOne hundred and forty-four patients were accrued. One hundred and thirty-six (66, SG1; 70, SG2) were evaluated for CRT-related toxicity. One hundred and twenty-seven (60, SG1; 67, SG2) were assessed for tumor response and surgical complications. A similar proportion of patients completed CRT per protocol in both SGs, but the cumulative dose of sensitizing 5-FU and radiation was higher in SG2. CRT-related toxicity was comparable between SGs. Average time from CRT-to-surgery was 6 (SG1) and 11 weeks (SG2). Pathologic complete response (pCR) was 18% (SG1) and 25% (SG2). Postoperative complications were similar between SGs.ConclusionsIntense neoadjuvant therapy consisting of CRT followed by additional chemotherapy (mFOLFOX-6), and delaying surgery may result in a modest increase in pCR rate without increasing complications in patients undergoing TME for locally advanced rectal cancer.

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

Publications

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

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