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Transfusion use and effect on progression-free, overall survival, and quality of life in upfront treatment of advanced epithelial ovarian cancer: evaluation of the European Organization for Research and Treatment EORTC-55971 Cohort
Prescott LS, Vergote I, Sun CC, Bodurka DC, Coleman RL
International journal of gynecological cancer : official journal of the International Gynecological Cancer Society. 2022
Abstract
BACKGROUND The impact of blood transfusion on ovarian cancer survival is uncertain. OBJECTIVE To investigate whether peri-operative blood transfusion negatively impacted progression-free survival, overall survival, and quality of life in patients with advanced ovarian cancer. METHODS We performed an ancillary analysis of the European Organization for Research and Treatment (EORTC) 55971 phase III trial, in which patients were randomized to primary debulking surgery versus neoadjuvant chemotherapy. Patients included in the per-protocol analysis were categorized by receipt of a transfusion. RESULTS 612 of 632 (97%) of patients had adequate data for analysis. Of those, 323 (53%) received a transfusion. The transfusion cohort was more likely to have had better Word Health Organization (WHO) performance status, serous histology, undergone primary debulking surgery, and received more aggressive surgery, with higher rates of no gross residual disease. Median overall survival was 34.0 vs 35.2 months in the no transfusion and transfusion cohorts (p=0.97). The adjusted HR for death was 1.18 (95% CI 0.94 to 1.48) in favor of the transfusion cohort. Median progression-free survival was 13.6 vs 12.6 months in the no transfusion and transfusion cohorts (p=0.96). The adjusted HR for progression was 1.14 (95% CI 0.91 to 1.43). There were no significant differences in global quality of life, fatigue, dyspnea, or physical functioning between the two cohorts at baseline or at any of the four assessment times. Grade 3 and 4 surgical site infections were more common in the transfusion cohort. CONCLUSION Transfusion did not negatively impact progression-free survival or overall survival; however, it was associated with increased peri-operative morbidity without improvements in quality of life.
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The impact of red blood cell transfusion on mortality and treatment efficacy in patients treated with radiation: A systematic review
Deschner M, Vasanthamohan L, Zayed S, Lazo-Langner A, Palma D, D'Souza D, Omar Gilani S, Gabriel Boldt R, Solh Z
Clinical and translational radiation oncology. 2022;33:23-29
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Editor's Choice
Abstract
INTRODUCTION Packed red blood cell (RBC) transfusion is frequently used in patients undergoing radiotherapy (RT) because retrospective data suggest that anemic patients may respond sub-optimally to RT. No high-quality evidence currently exists to guide transfusion practices and establish hemoglobin (Hb) transfusion thresholds for this patient population, and practice varies significantly across centers. This systematic review investigated whether maintaining higher Hb via transfusion in radiation oncology patients leads to improved outcomes. METHODS We performed a literature search of studies comparing RBC transfusion thresholds in radiation oncology patients. Included studies assessed patients receiving RT for malignancy of any diagnosis or stage. Excluded studies did not evaluate Hb or transfusion as an intervention or outcome. The primary outcome was overall survival. Secondary outcomes included locoregional control, number of transfusions and adverse events. RESULTS One study met inclusion criteria. The study pooled results from two randomized controlled trials that stratified anemic patients with head and neck squamous cell carcinoma to RBC transfusion versus no transfusion. The study found no significant differences in overall survival or locoregional control after five years, despite increased Hb levels in the transfused group. We conducted a narrative review by extracting data from 10 non-comparative studies involving transfusion in patients receiving RT. Results demonstrated no consistent conclusions regarding whether transfusions improve or worsen outcomes. CONCLUSIONS There is a lack of data on the effects of RBC transfusion on outcomes in patients undergoing RT. Well-designed prospective studies are needed in this area.
PICO Summary
Population
Patients undergoing radiotherapy (11 studies).
Intervention
Red blood cell transfusion.
Comparison
No transfusion.
Outcome
Only one study met the inclusion criteria which pooled results from two randomized controlled trials (DAHANCA 5 and 7). The study found no significant differences in overall survival or locoregional control after five years, despite increased haemoglobin levels in the transfused group (n= 235) vs. no transfused group (n= 230). A narrative review was conducted by extracting data from 10 other non-comparative studies involving transfusion in patients receiving radiotherapy. There were no consistent conclusions from these 10 studies on whether transfusions improve or worsen outcomes.
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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
Hung CM, Chen JJ, Zeng BY, Zeng BS, Chen YW, Suen MW, Wu MK, Tseng PT
Current oncology (Toronto, Ont.). 2021;28(4):3214-3226
Abstract
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.
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Blood transfusions may adversely affect survival outcomes of patients with lung cancer: a systematic review and meta-analysis
Cho S, Park J, Lee M, Lee D, Choi H, Gim G, Kim L, Kang CY, Oh Y, Viveiros P, et al
Translational lung cancer research. 2021;10(4):1700-1710
Abstract
BACKGROUND Despite common use in clinical practice, the impact of blood transfusions on prognosis among patients with lung cancer remains unclear. The purpose of the current study is to perform an updated systematic review and meta-analysis to evaluate the influence of blood transfusions on survival outcomes of lung cancer patients. METHODS We searched PubMed, Embase, Cochrane Library, and Ovid MEDLINE for publications illustrating the association between blood transfusions and prognosis among people with lung cancer from inception to November 2019. Overall survival (OS) and disease-free survival (DFS) were the outcomes of interest. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were computed using the random-effects model. Study heterogeneity was evaluated with the I(2) test. Publication bias was explored via funnel plot and trim-and-fill analyses. RESULTS We included 23 cohort studies with 12,175 patients (3,027 cases and 9,148 controls) for meta-analysis. Among these records, 22 studies investigated the effect of perioperative transfusions, while one examined that of transfusions during chemotherapy. Two studies suggested the possible dose-dependent effect in accordance with the number of transfused units. In pooled analyses, blood transfusions deleteriously influenced both OS (HR=1.35, 95% CI: 1.14-1.61, P<0.001, I(2)=0%) and DFS (HR=1.46, 95% CI: 1.15-1.86, P=0.001, I(2)=0%) of people with lung cancer. No evidence of significant publication bias was detected in funnel plot and trim-and-fill analyses (OS: HR=1.26, 95% CI: 1.07-1.49, P=0.006; DFS: HR=1.35, 95% CI: 1.08-1.69, P=0.008). CONCLUSIONS Blood transfusions were associated with decreased survival of patients with lung cancer.
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Restrictive versus liberal transfusion strategies in patients with malignant neoplasm -a meta-analysis of randomized controlled trials
Yang XX, Dai XC, Liu CX, Lu JH, Lin SY
Transfus Apher Sci. 2020;:102825
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Editor's Choice
Abstract
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.
PICO Summary
Population
Patients with malignant tumours (3 randomised controlled trials (RCTs) n= 587).
Intervention
Restrictive red blood cell transfusion strategy (n= 311).
Comparison
Liberal red blood cell transfusion strategy (n= 276).
Outcome
Restrictive transfusion strategies were not associated with all-cause mortality and other clinical outcomes in malignant tumours. Secondary outcomes reported included incidence of renal replacement therapy (2 RCTs, n=498; RR 1.38), myocardial infarction (RR 1.17) and intensive care unit readmission (RR 1.19).
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Perioperative transfusion and the prognosis of colorectal cancer surgery: a systematic review and meta-analysis
Pang QY, An R, Liu HL
World journal of surgical oncology. 2019;17(1):7
Abstract
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.
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Survival analysis of intraoperative blood salvage for patients with malignancy disease: A PRISMA-compliant systematic review and meta-analysis
Wu WW, Zhang WY, Zhang WH, Yang L, Deng XQ, Ou MC, Yang YX, Liu HB, Zhu T
Medicine. 2019;98(27):e16040
Abstract
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.
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How low should we go: a systematic review and meta-analysis of the impact of restrictive red blood cell transfusion strategies in oncology
Prescott LS, Taylor JS, Lopez-Olivo MA. Munsell MF, VonVille HM, Lairson DR, Bodurka DC
Cancer Treatment Reviews. 2016;46:1-8.
Abstract
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.
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Allogeneic blood transfusion and the prognosis of gastric cancer patients: Systematic review and meta-analysis
Sun C, Wang Y, Yao HS, Hu ZQ
International Journal Of Surgery. 2015;13:102-10.
Abstract
BACKGROUND Perioperative allogeneic blood transfusion (ABT) may be a deleterious predictor on the prognosis of gastric cancer (GC) for subjects who had undergone curative surgeries. In this article we proposed to figure out the effect of ABT with a systematic review and meta-analysis. METHODS Relevant articles were identified by searching Pubmed and Embase to March 2014. A random-effects model or fixed-effects model was used to calculate pooled odds ratios (ORs). Sensitivity analysis, meta-regression, stratified analysis, dose-response meta-analysis were conducted, and publication bias tested. RESULTS Eighteen studies (9120 GC patients) were included, of which 36.3% received transfusions. ABT was associated with increased all-cause mortality (OR, 2.17; 95% confidence interval [CI], 1.72-2.74; p < 0.001; I(2) = 75%). Sensitivity analysis showed significant changes in ORs while meta-regression had little influence on ORs. Galbraith plot revealed the OR reduced to 2.10 (95% CI, 1.86-2.37; p < 0.001) with tau(2) reduced to 0.00 and I(2) reduced to 0%. RESULTS of stratified analysis were robust and consistent. Dose-response meta-analysis revealed that all-cause mortality was significantly lower in patients transfused with <800 mL of blood than those transfused with >800 mL (OR, 0.58; 95% CI, 0.37-0.92; p = 0.02; I(2) = 54%). ABT was also associated with increased cancer-related mortality (OR, 2.57, p = 0.011) and recurrence (OR, 1.52, p = 0.017). CONCLUSIONS In GC patients undergoing curative surgeries, ABTs are associated with a worse prognosis, including all-cause mortality, cancer-related mortality and recurrence. Patient blood management should be investigated further to minimize use of ABT.Copyright © 2014 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.
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Transfusion requirements in surgical oncology patients: a prospective, randomized controlled trial
Pinheiro de Almeida J, Vincent JL, Barbosa Gomes Galas FR, Pinto Marinho de Almeida E, Fukushima JT, Osawa EA, Bergamin F, Lee Park C, Nakamura RE, Fonseca SM, et al
Anesthesiology. 2015;122((1):):29-38.
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Abstract
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.
Clinical Commentary
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) [1], following hip (FOCUS) [2] and cardiac surgery (TRACS) [3, 4], and patients with acute upper gastrointestinal bleeding [5] and sepsis (TRISS) [6]. Patients with cancer who are anaemic have poorer outcomes than those who are not [7] 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 [8]. 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 [4]; 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.
References
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.