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Preventing Colorectal Cancer Metastases following Surgical Removal of a Primary Tumor

ABSTRACT: Interventions: In the current study we aim at testing the safety and efficacy of our drug cocktail in patients undergoing excision of colorectal cancer. Both short-term outcomes (immune and endocrine indices), as well as 3-year recurrence rates will be assessed within patients. Specifically, we propose a double blind clinical trial with two major arms: (I) placebo treatment, and (II) treatment with a cocktail of a B-blocker (propranolol – to block catecholamines, oral tablet 40 mg , 3 times daily) and a COX2 inhibitor (etodolac – to block prostaglandin receptors, 200 mg oral tablets every 6 hours ). A total of 206 patients will be recruited. The drug treatment will be given for a total of 20-day period, commencing five days before surgery, with no time overlap with adjuvant therapy, and independently of any other routine therapy. The drug treatment is planned for only 15 post-operative days to reduce potential side effects, and because most immunological and endocrine perturbations induced by surgery dissipate during this period. Immune and endocrine baseline levels will be established in a group of thirty healthy matched control subjects. Short-term endocrine and immune measures will include: serum levels of various cytokines; serum cortisol, C-reactive protien, Vascular endothelial growth factor, leukocyte subpopulations and their functional markers; and Natural killar cells activity. All indices will be assessed repeatedly within subjects, using freshly drawn blood samples that will be collected twice before surgery (days -5 and on the morning of surgery), and on post-operative days 1 and 3. Resected malignant tumors and normal colonic tissue will be tested for catecolamines (CA) and prostaglandines (PG) receptor expression. Clinical outcomes will include perioperative complic Primary outcome(s): Tumor recurrence by abdominal CT scan and colonoscope[recurrence survey starts 6 months after surgery and then every 6 months for 2 years] Study Design: Purpose: Prevention; Allocation: Randomised controlled trial; Masking: Blinded (masking used);Assignment: Parallel

DISEASE(S): Colorectal Cancer,Cancer-bowel-back Passage (rectum) Or Large Bowel (colon)

PROVIDER: 2458554 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Project description:The short perioperative period (days to weeks around surgery) is characterized by stress-inflammatory responses, including catecholamines (CAs, e.g., adrenaline) and prostaglandins (PGs, e.g., prostaglandin-E2) release, and induce deleterious pro-metastatic effects. Animal studies implicated excess perioperative release of CAs and PGs in facilitating cancer progression by affecting the malignant tissue, its local environment, and anti-metastatic immune functions. Congruently, animal studies conducted by the investigators indicate that combined use of the beta-adrenergic blocker, propranolol, and the prostaglandins inhibitor, etodolac - but neither drug separately - efficiently prevented post-operative metastatic development. Two recently conducted clinical trials, conducted by the investigators, in three medical centers in Israel, recruiting breast (n=38) and colorectal (n=34) cancer patients, assessing the safety and short-term efficacy of perioperative propranolol and etodolac treatment. Drugs were well tolerated, without severe adverse events. Importantly, molecular/biological analyses of the excised primary tumor indicated that drug treatment caused promising anti-metastatic transformations, as well as improvements in immune and inflammatory indices. These included (i) decreased tumor cell capacity to migrate, (ii) reduced pro-metastatic capacity of the malignant tissue, and (iii) improvement in immune infiltrating into the tumor (Paper published in Clinical Cancer Research, 2017). Herein, the investigators propose to conduct a double-blind placebo-controlled two-arm Phase II clinical trial in 200 colorectal cancer patients undergoing curative surgery in Israel. A perioperative 20-day drug treatment will be initiated 5 days before surgery. Primary outcomes will include (i) 3-year disease-free-survival (DFS), and 5-year overall survival (OS); and (ii) biological markers in blood samples, and in the excised tumor tissue. Secondary outcomes will include safety indices and psychological measures of depression, anxiety, distress, and fatigue

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Preventing Colorectal Cancer Metastases following Surgical Removal of a Primary Tumor

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