Extended Peri-operative Tinzaparin to Improve Disease-free Survival in Patients With Resectable Colon Cancer (PERIOP-01)

• Overall Survival [ Time Frame: measured at 5 years ] [ Designated as safety issue: No ]
  Death from any cause
• Venous Thromboembolism events [ Time Frame: From randomization until 56 days post-surgery ] [ Designated as safety issue: No ]

  • 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 [ Time Frame: From randomization until 56 days post-surgery ] [ Designated as safety issue: Yes ]

  • Major surgical site bleeding events defined as bleeding at the surgical site associated with:

  1. requirement for ≥4 units of packed red blood cells
  2. a drop in Hb of >40 g/L during the first post-op week
  3. bleeding requiring re-operation
  4. fatal bleeding
• Major bleeding events (not including the surgical site) [ Time Frame: From randomization until 56 days post-surgery ] [ Designated as safety issue: Yes ]

  • Major bleeding events (not including the surgical site) defined as:

  1. fatal bleeding, and/or
  2. symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intraarticular or pericardial, or intramuscular with compartment syndrome, and/or,
  3. 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 [ Time Frame: From randomization to 56 days post-surgery ] [ Designated as safety issue: Yes ]

  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:

  1. medical intervention;
  2. an unscheduled contact with a physician;
  3. temporary cessation of anticoagulant treatment
• Transfusion requirements [ Time Frame: From randomization to 56 days post-surgery ] [ Designated as safety issue: No ]

  Transfusion requirements using the number of units transfused:

  1. Red blood cells
  2. Platelets (Adult dose)
  3. Frozen Plasma
• Correlative endpoints [ Time Frame: 9 years ] [ Designated as safety issue: No ]
  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 [ Time Frame: Measured from Day 0 until day 28 post-operatively ] [ Designated as safety issue: No ]
  Other post-operative (day 0 - day 28) complications as defined using the modified Clavien Classification

• Overall Survival [ Time Frame: measured at 5 years ] [ Designated as safety issue: No ]
  Death from any cause
• Venous Thromboembolism events [ Time Frame: Measured until 5 years post operatively ] [ Designated as safety issue: No ]

  • 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 ultrsonography 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 post-operative bleeding events [ Time Frame: Measured until 5 years post operatively ] [ Designated as safety issue: Yes ]

  • Major post-operative (during hospitalization) bleeding events defined as:

  1. requirement for ≥4 units of packed red blood cells
  2. a drop in Hb of >40 g/dL during the first post-op week
  3. bleeding requiring re-operation
  4. intracranial bleeding
  5. fatal bleeding
• Major bleeding events during follow-up [ Time Frame: Measured until 5 years post operatively ] [ Designated as safety issue: Yes ]

  Major bleeding events during follow-up defined as:

  1. fatal bleeding, and/or
  2. symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intraarticular or pericardial, or intramuscular with compartment syndrome, and/or,
  3. bleeding causing a fall in hemoglobin level of >20 g/L, or leading to transfusion of >2 units of whole blood or red cells
• Minor bleeding events [ Time Frame: Measured until 5 years post operatively ] [ Designated as safety issue: Yes ]
  Minor bleeding events prior to surgery, during surgery and during follow-up period and will be defined as any bleeding not meeting the requirements of a major bleeding event
• Transfusion requirements [ Time Frame: Measured until 5 years post operatively ] [ Designated as safety issue: No ]

  Transfusion requirements using the number of units transfused:

  1. Red blood cells
  2. Platelets (Adult dose)
  3. Frozen Plasma
• Correlative endpoints [ Time Frame: 9 years ] [ Designated as safety issue: No ]
  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 [ Time Frame: Measured from Day 0 until day 28 post-operatively ] [ Designated as safety issue: No ]
  Other post-operative (day 0 - day 28) complications as defined using the modified Clavien Classification

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 colon 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 colon cancer, it would improve the health and quality of life for these patients.

• 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 Name: Innohep
• 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 Name: Innohep

• 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.
  Intervention: Drug: Tinzaparin
• 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.
  Intervention: Drug: Tinzaparin

Inclusion Criteria:

- 1. Diagnosis of pathologically-confirmed invasive adenocarcinoma of the colon 2. Pre-operative work-up that reveals potential resectability (CT scan or MRI of the abdomen and pelvis within 90 days of randomization) 3. 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 within 90 days of randomization) 4. A planned surgical operation for resection of the colon cancer within 6 weeks from the date of randomization 5. ECOG performance status 0 or 1 6. Age ≥18 years 7. Hemoglobin ≥ 80g/L 8. Able and willing to sign Research Ethics Board (REB)-approved written consent form 9. Able and willing to comply with study procedures and follow-up examinations contained within the written consent form.

Exclusion Criteria:

- 1. Rectal adenocarcinoma (defined as tumour below the peritoneal reflection on imaging or within 15 cm of the anal verge by rigid sigmoidoscopy) 2. Carcinoma only present in a completely excised polyp (i.e. no residual tumour evident in the colon) 3. Prior VTE including deep vein thrombosis (DVT) or pulmonary embolism (PE) 4. Requirement for full dose peri-operative anticoagulation 5. Contraindication to heparin therapy

1. history of heparin induced thrombocytopenia (HIT)
2. platelet count of less than 100 x 109/L
3. actively bleeding
4. severe hypertension (SBP >200 and/or DBP >120) on more than one reading
5. documented peptic ulcer within 6 weeks
6. severe hepatic failure (INR >1.8)
7. creatinine clearance of < 30 ml/min as calculated by the Cockcroft-Gault formula
8. heparin or pork allergy
9. Other contraindication to anticoagulation 6. Geographic inaccessibility (less likely to comply with required follow-up visits and care) 7. Participating in another interventional trial that may result in co-intervention or contamination (to be determined by sponsor) 8. 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 9. Treatment, including radiation therapy, chemotherapy or targeted therapy, administered for the currently diagnosed colon cancer prior to randomization 10. Pregnant or lactating 11. Unable/unwilling to providing informed consent.