Can extended duration tinzaparin improve survival in localized invasive CRC?

Extended duration perioperative thromboprophylaxis with low molecular weight heparin tinzaparin (administered before and for 56 days after surgery) does not lead to longer disease-free survival at 3 years in patients with localized invasive colorectal cancer undergoing surgical resection, reports a study.

“The rates of clinically detected venous thromboembolism were low and extended duration thromboprophylaxis was not associated with a reduction in venous thromboembolism,” said the researchers, led by Rebecca C Auer, professor at the University of Ottawa, Ottawa Hospital Research Institute, Ontario, Canada.

This multicentre, open-label, randomized controlled trial was conducted in 12 hospital in Canada between 25 October 2011 and 31 December 2020. A total of 614 adults with pathologically confirmed invasive adenocarcinoma of the colon or rectum, without evidence of metastatic disease, and were scheduled to undergo surgical resection were enrolled.

Participants were randomly assigned to extended duration thromboprophylaxis (n=307) using daily subcutaneous tinzaparin 4,500 IU or to inpatient postoperative thromboprophylaxis only. Disease-free survival at 3 years was the primary outcome, while secondary ones included venous thromboembolism, postoperative major bleeding complications, and 5-year overall survival.

The researchers ceased trial recruitment prematurely following the interim analysis due to the ineffectiveness of the study drug. The primary outcome was achieved by 235 (77 percent) patients in the extended duration group and by 243 (79 percent) in the in-hospital thromboprophylaxis group (hazard ratio [HR], 1.1, 95 percent confidence interval [CI], 0.90‒1.33; p=0.4). [BMJ 2022;378:e071375]

Between-group difference

Five (2 percent) patients in the extended duration group and four (1 percent) in the in-hospital thromboprophylaxis group had postoperative venous thromboembolism (p=0.8). Major surgery-related bleeding in the first postoperative week occurred in one (<1 percent) patient in the extended duration group and in six (2 percent) in the in-hospital thromboprophylaxis group (p=0.1).

In addition, overall survival at 5 years did not significantly differ in 272 (89 percent) patients in the extended duration group and 280 (91 percent) in the in-hospital thromboprophylaxis group (HR, 1.12, 95 percent CI, 0.72‒1.76; p=0.1).

“The results of our study are consistent with the TILT and NVALT-8 trials, evaluating the effect of adjuvant tinzaparin and nadroparin in patients with resected stage II-III lung cancer where low molecular weight heparin had no effect on overall or disease-free survival,” the researchers said. [Eur Respir J 2018;52:1801220; Br J Cancer 2019;121:372-377]

More than half (53 percent) of the patients in the current trial received adjuvant chemotherapy. Preclinical studies have reported the antimetastatic properties of low molecular weight heparins, but this benefit has not been translated into clinical benefit, according to the researchers.

“The metastatic cascade and subsequent development of clinically detected recurrence is a complex process with a multitude of mechanistic interactions, and modifying one mechanism could simply be insufficient in any clinical setting,” the researchers said.

“Nonetheless, the immediate postoperative period remains an important window to prevent the development of metastatic disease and an area to explore novel treatments,” they added.