Efficacy of Different Interventions to Reduce Pre- or Perioperative Blood Transfusion Rate in Patients with Colorectal Cancer: A Network Meta-Analysis of Randomized Controlled Trials
Current oncology (Toronto, Ont.). 2021;28(4):3214-3226
BACKGROUND The high proportion of blood transfusions before and during surgery carries unnecessary risk and results in poor prognosis in colorectal cancer patients. Different pharmacological interventions (i.e., iron supplement or recombinant erythropoietin) to reduce blood transfusion rates have shown inconclusive results. METHODS This network meta-analysis (NMA) consisted of randomized controlled trials (RCTs) comparing the efficacy of different pharmacologic interventions (i.e., iron supplementation or recombinant erythropoietin) to reduce the blood transfusion rate. NMA statistics were conducted using the frequentist model. Results: Seven RCTs (688 participants) were included in this study. The NMA demonstrated that the combination of high-dose recombinant human erythropoietin and oral iron supplements was associated with the least probability of receiving a blood transfusion [odds ratio = 0.24, 95% confidence intervals (95% CIs): 0.08 to 0.73] and best reduced the amount of blood transfused if blood transfusion was necessary (mean difference = -2.62 U, 95% CI: -3.55 to -1.70 U) when compared to the placebo/control group. None of the investigated interventions were associated with any significantly different dropout rate compared to the placebo/control group. CONCLUSIONS The combination of high-dose recombinant human erythropoietin and oral iron supplements might be considered as a choice for reducing the rate of blood transfusion in patients with colorectal cancer. However, future large-scale RCT with long-term follow-up should be warranted to approve the long-term safety.
Restrictive versus liberal transfusion strategies in patients with malignant neoplasm -a meta-analysis of randomized controlled trials
Transfus Apher Sci. 2020;:102825
BACKGROUND Transfusion strategies are involving the survival and prognosis of patients with malignant neoplasm and the rational utilization of medical resources, but there are still controversy between different transfusion strategies. The aim of this article is to compare the benefit and harm of restrictive and liberal red blood cell (RBC) transfusion strategies in patients with malignant tumors. METHODS We searched articles in the databases of PubMed, Cochrane Library, Web of Science, Embase and major conference proceedings, identified all randomized controlled trials (RCTs) and compared restrictive transfusion strategies with those that are liberal until MARCH 18, 2019. We used risk ratio (RR) and and 95 % confidence interval (95 %CI) to calculate the results of dichotomous variables, and the study heterogeneity was assessed by using the I(2) statistics. Also, we did sensitivity analysis and quality assessment. RESULTS Restrictive transfusion policies appear to have no effect on all-cause mortality (RR 1.33; 95 % CI 0.74-2.38; P = 0.34), compared with liberal policies. 2 trials including 498 patients were included of renal replacement therapy (RR 1.38; 95 % CI, 0.73-2.59; P = 0.32; I(2) = 0%). Myocardial infarction (RR 1.17; 95 % CI, 0.33-4.1; P = 0.81; I(2) = 0%) and ICU readmission were also mentioned in these articles (RR 1.19; 95 % CI, 0.7-2.04; P = 0.52; I(2) = 0%). However, the RR of hospital length can't be evaluated. CONCLUSION Restrictive transfusion strategies were not associated with all-cause mortality and other clinical outcomes in malignant tumors, and may be more suitable for patients' quality of life and medical economy than liberal.
Survival analysis of intraoperative blood salvage for patients with malignancy disease: A PRISMA-compliant systematic review and meta-analysis
BACKGROUND Intraoperative blood salvage as a blood-saving strategy has been widely used in surgery. Considering its theoretic risk of malignant tumor cells being reinfused and the corresponding blood metastases, the safety of intraoperative blood salvage in cancer surgery remains controversial. METHODS Following the Preferred Reporting Items for Systemic Review and Meta-Analysis (PRISMA), we searched the Cochrane Library, MEDLINE and EMBASE to November 2017. We included only studies comparing intraoperative blood salvage with allogeneic blood transfusion. RESULTS This meta-analysis included 9 studies with 4354 patients with 1346 patients in the intraoperative blood salvage group and 3008 patients in the allogeneic blood transfusion group. There were no significant differences in the 5-year overall survival outcome (odds ratio [OR] 1.12; 95% confidence interval [CI], 0.80-1.58), 5-year disease-free survival outcome (OR 1.08; 95% CI 0.86-1.35), or 5-year recurrence rate (OR 0.86; 95% CI 0.71-1.05) between the 2 study groups. Subgroup analysis also showed no significant differences in the 5-year overall survival outcome (OR 0.97; 95% CI 0.57-1.67) of hepatocellular carcinoma patients in liver transplantation. CONCLUSIONS For patients with malignant disease, intraoperative blood salvage did not increase the tumor recurrence rate and had comparable survival outcomes with allogeneic blood transfusion.
Perioperative transfusion and the prognosis of colorectal cancer surgery: a systematic review and meta-analysis
World journal of surgical oncology. 2019;17(1):7
BACKGROUND Perioperative transfusion can reduce the survival rate in colorectal cancer patients. The effects of transfusion on the short- and long-term prognoses are becoming intriguing. OBJECTIVE This systematic review and meta-analysis aimed to define the effects of perioperative transfusion on the short- and long-term prognoses of colorectal cancer surgery. RESULTS Thirty-six clinical observational studies, with a total of 174,036 patients, were included. Perioperative transfusion decreased overall survival (OS) (hazard ratio (HR), 0.33; 95% confidence interval (CI), 0.24 to 0.41; P < 0.0001) and cancer-specific survival (CSS) (HR, 0.34; 95% CI, 0.21 to 0.47; P < 0.0001), but had no effect on disease-free survival (DFS) (HR, 0.17; 95% CI, - 0.12 to 0.47; P = 0.248). Transfusion could increase postoperative infectious complications (RR, 1.89, 95% CI, 1.56 to 2.28; P < 0.0001), pulmonary complications (RR, 2.01; 95% CI, 1.54 to 2.63; P < 0.0001), cardiac complications (RR, 2.20; 95% CI, 1.75 to 2.76; P < 0.0001), anastomotic complications (RR, 1.51; 95% CI, 1.29 to 1.79; P < 0.0001), reoperation(RR, 2.88; 95% CI, 2.05 to 4.05; P < 0.0001), and general complications (RR, 1.86; 95% CI, 1.66 to 2.07; P < 0.0001). CONCLUSION Perioperative transfusion causes a dramatically negative effect on long-term prognosis and increases short-term complications after colorectal cancer surgery.
Influence of perioperative leukodeplated red blood cell transfusion on immune function of patients with bladder cancer
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi = Chinese Journal of Cellular and Molecular Immunology. 2018;34((7)):632-636.
Objective To investigate the effect of leukodeplated red blood cell (RBC) transfusion on immune function of patients with bladder cancer. Methods A total of 48 patients with bladder cancer who required perioperative RBC transfusion were randomized into two groups: 22 received leukodeplated RBC transfusion (Group I) and 26 received suspended RBC transfusion (Group II ). T-cell subgroup, natural killer cell activity, erythrocyte-C3b receptor rosette formation rate, and immunosuppressive acidic protein (IAP) level were determined for the two groups before and after transfusion, and the results were statistically analyzed. Results There was no obvious difference in immune function between the two groups before transfusion. After transfusion, the immune function of both groups was lower. However, it was higher in Group I than in Group II . IAP level was higher after transfusion than before transfusion; however, it was lower in Group I than in Group II . Conclusion Perioperative RBC transfusion can decrease immune function in patients with bladder cancer. Compared with suspended RBC transfusion, leukodeplated RBC transfusion can improve immune function in patients with bladder cancer.
The prognostic role of perioperative allogeneic blood transfusions in gastric cancer patients undergoing curative resection: A systematic review and meta-analysis of non-randomized, adjusted studies
European Journal of Surgical Oncology : the Journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology. 2018;44((4):):404-419
The impact of allogeneic perioperative blood transfusions (APTs) on the prognosis of gastric cancer patients undergoing curative-intent gastrectomy is still a highly debated topic. Two meta-analyses were published in 2015, and new studies report conflicting results. A literature review was conducted using PubMed, Scopus, the Cochrane Central Register of Controlled Trials and the Cochrane Database of Systematic Reviews, updated to March 1, 2016. Thirty-eight non-randomized studies reporting data on overall survival (OS), disease-free survival (DFS), disease-specific survival (DSS) and postoperative complications (PCs) were included. An inverse variance random-effects meta-analysis was conducted. APTs showed an association with worse OS, DFS, DSS and an increased number of PCs. The hazard ratio (HR) for OS was 1.49, with a 95% confidence interval (95% CI) of 1.32-1.69 (p < .00001; Q-test p = .001, I-squared = 56%). After outlier exclusion, the HR for OS was 1.34 (95% CI = 1.23-1.45, p < .00001; Q-test p = .64, I-squared = 0%). The HR for DFS was 1.48 (95% CI = 1.18-1.86, p = .0007; Q-test p = .31, I-squared = 16%), and the HR for DSS was 1.66 (95% CI = 1.5-2.19, p = .0004; Q-test p = .96, I-squared = 0%). The odds ratio for PCs was 3.33 (95% CI = 2.10-5.29, p < .00001; Q-test p = .14, I-squared = 42%). This meta-analysis showed a significant association between transfusions and OS, DFS, DSS and PCs. The quality of the evidence was low. Aggregation, selection and selective reporting bias were detected. The biases shifted the results towards significance. Further studies using accurate adjustment methods are needed. Until such additional studies are performed, caution in administering transfusions and optimization of cancer patient blood management are warranted.
Randomised feasibility study of a more liberal haemoglobin trigger for red blood cell transfusion compared to standard practice in anaemic cancer patients treated with chemotherapy
Transfusion Medicine (Oxford, England). 2017;28((3):):208-215
OBJECTIVES The primary objective of this feasibility study was to identify quality of life (QoL) scores and symptom scales as tools for measuring patient-reported outcomes (PRO) associated with haemoglobin level in chemotherapy-treated cancer patients. Secondary objectives included comparing QoL and symptoms between randomisation arms. BACKGROUND Anaemia in cancer patients undergoing chemotherapy is associated with decreased QoL. One treatment option is red blood cell transfusion (RBCT). However, the optimal haemoglobin trigger for transfusion is unknown. METHODS Patients were randomised to a haemoglobin trigger for RBCT of either < 9.7 g dL-1 (arm A) or < lower normal level, female: 11.5 g dL-1 , male: 13.1 g dL-1 (arm B). Four PROs were used: Functional Assessment of Cancer Therapy-General (FACT-G) and the FACT-Anaemia (FACT-An), a Numeric Rating Scale on symptoms of anaemia and self-reported Performance Status (PS). The association between haemoglobin and PRO variables was assessed using a linear mixed model with random effects. RESULTS A total of 133 patients were enrolled, of which 86 patients received RBCT (28 in arm A, 58 in arm B). Baseline questionnaires were filled out in 79.7% of cases. Haemoglobin levels were significantly correlated with FACT-An, FACT-An Total Outcome Index (TOI), Functional Well-Being, fatigue and PS. Improvement on several PRO variables was observed in both arms after RBCT, with clinically minimal important differences observed in FACT-G, Physical Well-Being, FACT-An, FACT-An TOI, fatigue and dyspnoea. CONCLUSIONS QoL scores of physical and functional domains as well as self-reported anaemia-related symptoms correlated well with haemoglobin level in chemotherapy-treated cancer patients.
Transfusion of irradiated red blood cell units with a potassium adsorption filter: A randomized controlled trial
BACKGROUND The irradiation of red blood cells (RBCs) causes damage of the RBC membrane with increased potassium (K) leak during storage compared with nonirradiated RBC units of similar age. A previous in vitro study showed a mean reduction of K of 94 +/- 5% with a potassium adsorption filter (PAF). STUDY DESIGN AND METHODS A prospective, single-center, nonblinded, randomized controlled trial (RCT) was designed to evaluate the safety and efficacy of transfusing irradiated RBC units with the PAF. Patients 18 years of age or older who received irradiated RBC units due to chemotherapy-induced anemia were randomly assigned to receive irradiated RBC units with the PAF (PAF group) or with the standard blood infusion set (control group). Primary outcome measures were safety and efficacy of the PAF (absolute change in hemoglobin [Hb] and K, respectively, in patient's blood values after transfusing the irradiated RBC units with or without the PAF). RESULTS A total of 63 irradiated RBC units were transfused to 17 patients in the control group, and a total of 56 irradiated RBC units were transfused to 13 patients in the PAF group. The absolute change of Hb (9.3 +/- 6.3 g/L vs. 8.1 +/- 5.8 g/L; p = 0.3) and the absolute change of K (-0.01 +/- 0.4 mmol/L vs. -0.01 +/- 0.3 mmol/L; p = 0.2) were comparable between the two groups of the trial. CONCLUSION The transfusion of 1 irradiated RBC unit with the PAF was as safe and efficacious as the transfusion of 1 irradiated RBC unit with the standard blood infusion set in patients with chemotherapy-induced anemia.
How low should we go: a systematic review and meta-analysis of the impact of restrictive red blood cell transfusion strategies in oncology
Cancer Treatment Reviews. 2016;46:1-8.
BACKGROUND Most non-oncologic clinical practice guidelines recommend restrictive allogeneic blood transfusion practices; however, there is a lack of consensus regarding the best transfusion practice in oncology. We conducted a systematic review of the literature to compare the efficacy and safety of restrictive versus liberal transfusion strategies in patients with cancer. METHODS A literature search using MEDLINE, PUBMED and EMBASE identified all controlled studies comparing the use of restrictive with liberal transfusion in adult oncology participants up to August 10, 2015. Two review authors independently assessed studies for inclusion, extracted data and appraised the quality of the included studies. The primary outcomes of interest were blood utilization and all-cause mortality. RESULTS Out of 4241 citations, six studies (3 randomized and 3 non-randomized) involving a total of 983 patients were included in the final review. The clinical context of the studies varied with 3 chemotherapy and 3 surgical studies. The overall risk of bias in all studies was moderate to high. Restrictive transfusion strategies were associated with a 36% reduced risk of receiving a perioperative transfusion (risk ratio (RR) 0.64, 95% confidence interval (CI) 0.49-0.83). There was no difference in mortality between the strategies (RR 1.00, 95% CI 0.32-3.18). There were no differences in adverse events reported between the restrictive and liberal transfusion strategies. CONCLUSION Restrictive strategy appears to decrease blood utilization without increasing morbidity or mortality in oncology. This review is limited by a paucity of high quality studies on this topic. Better designed studies are warranted.
Transfusion requirements in surgical oncology patients: a prospective, randomized controlled trial
BACKGROUND Several studies have indicated that a restrictive erythrocyte transfusion strategy is as safe as a liberal one in critically ill patients, but there is no clear evidence to support the superiority of any perioperative transfusion strategy in patients with cancer. METHODS In a randomized, controlled, parallel-group, double-blind (patients and outcome assessors) superiority trial in the intensive care unit of a tertiary oncology hospital, the authors evaluated whether a restrictive strategy of erythrocyte transfusion (transfusion when hemoglobin concentration <7 g/dl) was superior to a liberal one (transfusion when hemoglobin concentration <9 g/dl) for reducing mortality and severe clinical complications among patients having major cancer surgery. All adult patients with cancer having major abdominal surgery who required postoperative intensive care were included and randomly allocated to treatment with the liberal or the restrictive erythrocyte transfusion strategy. The primary outcome was a composite endpoint of mortality and morbidity. RESULTS A total of 198 patients were included as follows: 101 in the restrictive group and 97 in the liberal group. The primary composite endpoint occurred in 19.6% (95% CI, 12.9 to 28.6%) of patients in the liberal-strategy group and in 35.6% (27.0 to 45.4%) of patients in the restrictive-strategy group (P = 0.012). Compared with the restrictive strategy, the liberal transfusion strategy was associated with an absolute risk reduction for the composite outcome of 16% (3.8 to 28.2%) and a number needed to treat of 6.2 (3.5 to 26.5). CONCLUSION A liberal erythrocyte transfusion strategy with a hemoglobin trigger of 9 g/dl was associated with fewer major postoperative complications in patients having major cancer surgery compared with a restrictive strategy.
What is known?
Thresholds for red cell transfusion are currently under much scrutiny with a growing number of randomised controlled trials (RCTs) supporting the safety of restrictive transfusion practices in specified patient groups e.g. patients treated on the intensive care unit (TRICC) , following hip (FOCUS)  and cardiac surgery (TRACS) [3, 4], and patients with acute upper gastrointestinal bleeding  and sepsis (TRISS) . Patients with cancer who are anaemic have poorer outcomes than those who are not  but there are no previous RCTs examining risks and benefits of transfusion in surgical patients with malignancy.
What did this paper set out to examine?
This paper describes 198 critically ill patients following surgery for abdominal malignancy randomised to restrictive (threshold 7 g/dl) and liberal (9 g/dl) transfusion strategies . The primary outcome was a composite 30-day endpoint of all-cause mortality, cardiovascular complications, acute respiratory distress syndrome, acute kidney injury requiring renal replacement therapy, septic shock and reoperation.
What did they show?
This is the first RCT to demonstrate a worse outcome for patients assigned a restrictive threshold. There is an almost two-fold increase in the composite 30-day endpoint in the restrictive group (35.6% versus 19.6%, p=0.012). Thirty day mortality was 8.2% (liberal) versus 22.8% (restrictive), p= 0.005. The most common causes of death were septic shock and multisystem organ failure. Cardiovascular events and intra-abdominal sepsis were more frequent in the restrictive group.
The extent of the worse outcomes in the restrictive group is unexpected following larger RCTs supporting the safety of restrictive transfusion practice. The least supportive of this strategy was the recently published cardiac surgery RCT which concluded that a restrictive threshold was not superior to a liberal threshold ; they showed no difference in the primary outcome (serious infection or ischaemic event at 3 months). However, there was an increased mortality in the restrictive group (4.2% versus 2.6%, p=0.045).
There are significant differences in outcomes between the 2 groups in Almeida’s study and so we must consider whether these are attributable to differences in transfusion practice. Importantly, 57.7% of those even in the liberal group (79.2% in the restrictive group) were not transfused during the randomisation period. The reported difference in haemoglobin between the groups relates to the pre-transfusion haemoglobin and therefore does not include haemoglobins of those not transfused (68.9% of total study population).
Although the target thresholds were 7.0 and 9.0 g/dl, patients were transfused on average at 6.8 g/dl (restrictive group) and 7.9 g/dl (liberal). Compared to the preceding large RCTs there is a lack of separation in haemoglobin levels between groups [2, 6]. All 13 protocol deviations in the liberal group occurred when patients with haemoglobin <9.0 g/dl were not transfused; all 7 deviations in the restrictive group were for transfusions given with haemoglobin >7.0 g/dl.
The median duration for which patients remained randomised (i.e. length of ICU stay) was 4 days, compared to 11 days in the TRICC trial and until discharge or death in the Villanueva and FOCUS trials. In this study the small difference in haemoglobin between the groups only emerges at 4 days.
These factors together call into doubt whether the differences in outcomes can be attributed to differences in transfusion alone, and so an alternative explanation for the differences in outcomes must be sought. One possible reason is the small excess in major operations (oesophagectomy, gastroduodenopancreatectomy) as compared to cystectomy and hysterectomy in the restrictive group; this may also explain the excess of abdominal sepsis. There was a small, non-significant, excess of patients with diabetes, chronic obstructive pulmonary disease and congestive heart failure in the restrictive group.
The question addressed in the study is important and there are positive aspects to the trial which should be highlighted. This is the first randomised study specifically assessing post-operative patients with malignancy; the FOCUS study is the only other large RCT to include significant numbers of cancer patients (18.0 and 18.8% in the two arms) but the types, stage or remission status are not given. In the current study there were attempts to blind patients and investigators and the clinical practice described is deliverable on most ICUs. There were small numbers of protocol deviations and follow-up to the primary endpoint was complete.
What are the implications for practice and for future work?
It is important to consider the limitations of this study if its findings are to be used to inform practice. In the presence of multiple other RCT data supportive of restrictive transfusion practice we would caution against changing practice based on this research. Despite its unexpected findings, this study questions the safety of restrictive transfusion practice and it is important that future trials continue to address the safety this approach among different patient groups.
1. Hébert PC, et al., A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group. N Engl J Med, 1999. 340(6): 409-17.