PERIOP-01: Extended Peri-operative Tinzaparin to Improve Disease-free Survival in Patients With Resectable Colorectal Cancer
Study Details
Study Description
Brief Summary
The human body has a natural stress response to surgery, including the formation of blood clots. This response to surgery has been shown to increase metastases (the spread of cancer cells to other organs in the body). These metastases cannot be seen at the time of surgery but when they grow into new tumors, the cancer has recurred (come back). A blood thinner called "low molecular weight heparin" (LMWH) can suppress the development of metastases after surgery in animal experiments. The investigators want to see if giving patients with colorectal cancer the blood thinner, LMWH, around the time of surgery can decrease the chance of their cancer spreading to other organs (metastases) and coming back (recurrence).
The investigators need 1075 patients to answer our scientific question. Patients who give informed consent will be randomly put into one of two groups, the experimental group and the control group. The patients in the control group will be treated with LMWH starting a few hours after surgery and every day until they leave the hospital. This is how most patients are treated after colon cancer surgery (standard care). The patients in the experimental group will be treated with LMWH for a longer period of time, starting on the day they agree to have surgery and continuing for two months after surgery. All the patients will be followed for at least three years after surgery to find out if their cancer has recurred (come back). If LMWH treatment around the time of surgery reduces the chance of recurrence in patients with colorectal cancer, it would improve the health and quality of life for these patients.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 3 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Extended peri-operative thromboprophylaxis The experimental arm will receive a subcutaneous injection of 4,500 IU of tinzaparin daily beginning at randomization and continued for 56 days following resection. There will be a minimum of one dose of pre-operative LMWH since it is not reasonable to delay surgery for the purpose of administering LMWH. The maximum duration of pre-operative LMWH will be 6 weeks. |
Drug: Tinzaparin
The experimental arm will receive a subcutaneous injection of 4,500 IU of tinzaparin daily beginning at randomization and continued for 56 days following resection. There will be a minimum of one dose of pre-operative LMWH since it is not reasonable to delay surgery for the purpose of administering LMWH. The maximum duration of pre-operative LMWH will be 6 weeks.
Other Names:
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| Active Comparator: Standard thromboprophylaxis The control arm will receive a daily subcutaneous injection of 4,500 IU of tinzaparin beginning with the first post-operative dose and continued for the duration of hospitalization. |
Drug: Tinzaparin
The control arm will receive a daily subcutaneous injection of 4,500 IU of tinzaparin beginning with the first post-operative dose and continued for the duration of hospitalization.
Other Names:
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Outcome Measures
Primary Outcome Measures
- Disease Free Survival [measured at 3 years]
Disease free survival is measured from the time of randomization until local disease recurrence, distant disease recurrence, a new primary colon cancer malignancy, other second primary cancer or death from any cause.
Secondary Outcome Measures
- Overall Survival [measured at 5 years]
Death from any cause
- Venous Thromboembolism events [From randomization until 56 days post-surgery]
• VTE events defined as: a. Deep vein thrombosis: i. non-compressibility of any vein segment from the common femoral vein to the trifurcation of the popliteal vein on compressive ultrasonography ii.persistent intra-luminal filling defect of the iliac, common femoral, superficial femoral, popliteal, posterior tibial or peroneal veins on contrast venography b. Pulmonary embolism: i.high probability V/Q scan ii.positive pulmonary angiogram iii.spiral CT demonstrating intraluminal filling defect in a vessel larger than a segmental artery
- Major surgical site bleeding events [From randomization until 56 days post-surgery]
• Major surgical site bleeding events defined as bleeding at the surgical site associated with: requirement for ≥4 units of packed red blood cells a drop in Hb of >40 g/L during the first post-op week bleeding requiring re-operation fatal bleeding
- Major bleeding events (not including the surgical site) [From randomization until 56 days post-surgery]
• Major bleeding events (not including the surgical site) defined as: fatal bleeding, and/or symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intraarticular or pericardial, or intramuscular with compartment syndrome, and/or, bleeding causing a fall in hemoglobin level of ≥20 g/L, or leading to transfusion of ≥2 units of whole blood or red cells.
- • Clinically relevant bleeding events prior to surgery and during the • Clinically relevant bleeding events [From randomization to 56 days post-surgery]
Clinically relevant bleeding events prior to surgery and during the follow-up period will be defined as overt bleeding episodes not meeting the inclusion for major bleeding but associated with one of the following: medical intervention; an unscheduled contact with a physician; temporary cessation of anticoagulant treatment
- Transfusion requirements [From randomization to 56 days post-surgery]
Transfusion requirements using the number of units transfused: Red blood cells Platelets (Adult dose) Frozen Plasma
- Correlative endpoints [5 years]
The correlative endpoints seek to evaluate the pro-metastatic mechanisms of surgery and the antimetastatic mechanisms of LMWH in subjects undergoing surgical resection for colon cancer.
- Other post-operative (day 0 - day 28) complications [Measured from Day 0 until day 28 post-operatively]
Other post-operative (day 0 - day 28) complications as defined using the modified Clavien Classification
Eligibility Criteria
Criteria
Inclusion Criteria:
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Diagnosis of pathologically-confirmed invasive adenocarcinoma of the colon or rectum
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Pre-operative work-up that reveals potential resectability (CT scan or MRI of the abdomen and pelvis) with resection planned within 6 weeks of date of randomization
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Pre-operative work-up that reveals no evidence of metastatic disease (CT scan or MRI of the abdomen and pelvis and chest X-ray (CXR) or CT scan of the chest)
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Age ≥18 years
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Hemoglobin ≥ 80g/L
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Able and willing to comply with study procedures and follow-up examinations contained within the written consent form.
Exclusion Criteria:
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Carcinoma only present in a completely excised polyp (i.e. no residual tumour evident in the colon)
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Prior VTE including deep vein thrombosis (DVT) or pulmonary embolism (PE)
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Requirement for full dose peri-operative anticoagulation
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Contraindication to heparin therapy
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history of heparin induced thrombocytopenia (HIT)
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platelet count of less than 100 x 109/L
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actively bleeding
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severe hypertension (SBP >200 and/or DBP >120) on more than one reading
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documented peptic ulcer within 6 weeks
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severe hepatic failure (INR >1.8)
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creatinine clearance of < 30 ml/min as calculated by the Cockcroft-Gault formula
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Other contraindication to anticoagulation
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Participating in another interventional trial that may result in co-intervention or contamination (to be determined by sponsor)
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History of other malignancies (except for adequately treated basal or squamous cell carcinoma or carcinoma in situ) within 5 years of the colorectal cancer diagnosis
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Pregnant or lactating
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Unable/unwilling to providing informed consent.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Ghent University Hospital | Ghent | Belgium | ||
| 2 | Hamilton Health Sciences Corporation | Hamilton | Ontario | Canada | L8L 8E7 |
| 3 | Kingston General Hospital | Kingston | Ontario | Canada | |
| 4 | London Health Research Institute | London | Ontario | Canada | N6C 2R5 |
| 5 | The Ottawa Hospital | Ottawa | Ontario | Canada | K1H 8L6 |
| 6 | Montfort Hospital | Ottawa | Ontario | Canada | |
| 7 | Queensway Carleton Hospital | Ottawa | Ontario | Canada | |
| 8 | Sault Area Hospital | Sault Ste. Marie | Ontario | Canada | |
| 9 | Health Sciences North | Sudbury | Ontario | Canada | |
| 10 | Humber River Hospital | Toronto | Ontario | Canada | M3M 0B2 |
| 11 | Mount Sinai Hospital | Toronto | Ontario | Canada | |
| 12 | North York General Hospital | Toronto | Ontario | Canada | |
| 13 | St. Joseph's Health Centre | Toronto | Ontario | Canada | |
| 14 | Sunnybrook Health Science Centre | Toronto | Ontario | Canada | |
| 15 | Jewish General Hospital | Montreal | Quebec | Canada | |
| 16 | CHRU Brest | Brest | France |
Sponsors and Collaborators
- Ottawa Hospital Research Institute
Investigators
- Principal Investigator: Marc Carrier, MD, Ottawa Hospital Research Institute
- Principal Investigator: Rebecca Ann Auer, MD, Ottawa Hospital Research Institute
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 221097