Allogeneic blood transfusion and cancer recurrence: 20 years later

I n 1981, Gantt formulated the hypothesis that perioperative allogeneic blood transfusion (ABT) might be associated with an increase in the recurrence rate of resected malignancies by means of a down regulation of the immune response of a human host to a tumor. Well over 100 observational studies were published in the 1980s and 1990s, reporting on patients with resected malignancies and comparing the recurrence rate, cancer-specific mortality (or disease-free survival), and/or all-cause mortality (or overall survival), between patients receiving or not receiving perioperative ABT. The need for perioperative ABT reflects a patient’s overall severity of illness—a confounding factor impossible to control completely by statistical methods and reflecting the grand total of patient comorbidities, disease burden, and perioperative complications. In 1992 Ness and coworkers greatly improved the design and validity of the observational studies by prospectively comparing recipients of allogeneic versus autologous blood (as opposed to retrospectively reviewing transfused vs. untransfused patients). Two comparisons of subjects randomly assigned to receive allogeneic versus autologous blood, and one of subjects randomly assigned to receive nonleukoreduced versus leukoreduced ABT (in the event that they needed perioperative transfusion for resection of colorectal cancer) followed in 1993 to 1994. The latter randomized controlled trials (RCTs) were medically and statistically homogeneous, with the proportion of patients who received transfusion varying from 59% to 75% among the studies and the proportion of patients developing recurrent cancer varying from 23% to 25.5%. Accordingly, the findings of the three RCTs were integrated in two meta-analyses that found no increase in colorectal cancer recurrence attributable to nonleukoreduced ABT (summary relative risk [RR], 1.04; 95% confidence interval, 0.81-1.35). Both meta-analyses cautioned that the possibility of an adverse ABT effect smaller than a 33% or 20% increase in the risk of cancer recurrence secondary to nonleukoreduced ABT could not be ruled out. In addition, if the adverse ABT effects were mediated by allogeneic white blood cells (WBCs), the dose of ABT used in each RCT could have been insufficient for causing the adverse effect, because all three RCTs had administered buffy coat–reduced blood (with approx. two-thirds of its donor WBCs removed) to their nonleukoreduced ABT arm. Thus, the average red blood cell (RBC) dose given in these studies (e.g., a median of 3 RBC units in the RCT of Houbiers et al.) was equivalent, in terms of allogeneic WBC content, to 1 US unit of nonleukoreduced RBCs. Finally, all three RCTs had enrolled patients with colorectal cancer, despite the fact that the existence of a specific immune response to colorectal cancer cells had not been established. Although it is possible to generate cytotoxic T cells in vitro that recognize antigens expressed by colorectal cancer cells, the relevance of these cytotoxic cells in tumor growth may be limited because of a loss of the expression of HLA molecules and adhesion molecules on the colorectal cancer cells. Virus-associated cancers are considered immunogenic. By the time of the meta-analysis of Brand and Houbiers, the association between ABT and cervical cancer recurrence had been investigated in six observational studies that had included more than 1000 women. Although the low overall recurrence rate in the six studies precluded a definitive conclusion, no adverse ABT effect was detected across the six studies. These results were possibly due to the fact that, in the development of cervical intraepithelial neoplasia, the expression of HLA Class I molecules on malignant cells is specifically down regulated. Human papillomavirus–specific cytotoxic cells (whose function might potentially be suppressed by ABT) may thus not be effective against cervical cancer cells because of this reduction in Class I HLA molecule expression. The nonsignificant and small RR of colorectal cancer recurrence secondary to nonleukoreduced ABT across the three RCTs dampened the enthusiasm for investigating this purported ABT effect by means of RCTs and also by means of observational studies. Between patients with gastric cancer randomly assigned to receive nonleukoreduced versus leukoreduced ABT, there was no difference in survival or cancer recurrence. Observational studies continued to generate debate by sometimes reporting significant associations of nonleukoreduced ABT with cancer recurrence, cancer-specific mortality, and/or all-cause mortality, until two recent metaanalyses of ABT and adverse clinical outcomes in colorectal cancer and hepatocellular cancer resurrected the controversy about a purported adverse ABT effect. © 2014 AABB