Peri-Operative Blood Transfusion Does Not Influence Overall and Disease-Free Survival After Radical Gastrectomy for Stage II/III Gastric Cancer: a Propensity Score Matching Analysis

The fourth most frequently occurring cancer worldwide is gastric cancer (GC) and is the second most frequent cause of cancer mortality in China,1,2 with radial surgery as the only possible curative treatment to date. Unfortunately, the majority of patients in China and Western countries are diagnosed at an advanced stage, with radical gastrectomy with D2 lymphadenectomy the recommended treatment in the guidelines for these patients in the East and West.3‐5 A large number of patients with GC present with anemia on hospital admission, and furthermore, gastrectomy with lymph node dissection sometimes causes massive intra-operative blood loss even performed by experienced surgeons.6,7 Thus, blood transfusions (BTF) can be a life-saving treatment during D2 gastrectomy for advanced GC, although the need for BTF is decreasing as a result of improvements in surgical techniques and peri-operative care.8 While BTF may be vital in some circumstances, there is a growing body of evidence that BTF produces adverse actions on the prognosis in GC patients who had gastrectomy operations to cure GC.9‐12 Transfusion-related immunomodulation (TRIM) and systemic inflammation have been considered to play a pivotal role in these detrimental effects.13 However, other scholars have argued that BTF is a confounding factor rather than a prognostic indicator because it was obviously affected by other variables.14‐17 Thus, the association between BTF and oncological outcomes of GC remains controversial. We hypothesize that decreased long-term survival for GC patients who received BTF is not necessarily because of BTF, but maybe due to the extent of the patient’s tumor and other prognostic factors related to BTF, such as advanced age, difficulty and duration of surgical procedure, and an advanced tumor stage.9 This question was addressed by conducting a retrospective study to investigate the association between BTF and overall survival (OS) and disease-free survival (DFS) following radical gastrectomy for stage II/III GC using the database from a high volume center in China. Multivariate Cox regression and propensity score matching (PSM) analyses were utilized to determine any links.

Although a number of studies have investigated the impact of peri-operative BTF on the oncological outcomes of GC patients after curative resection, the conclusions are contradictory and even confusing.10,12,14‐17 Squires et al.10 conducted an analysis of 765 patients in seven institutions from the US Gastric Cancer Collaborative and concluded that BTF was significantly linked to a lower DFS and OS of patients with GC, independent of adverse clinicopathological factors. Another multi-center retrospective study of 927 patients reported that BTF did not influence prognosis of those with stage I–IV GC.17 A possible explanation for the conflicting results was the inconsistency in patient inclusion criteria. Thus, it seems difficult to determine the effects of BTF on the long-term survival rates of patients having stage I GC, who experience very low rates of receiving BTF but have significantly longer long-term survival times.10,14,16,17 Even patients with stage IV GC, who experienced extremely disappointing survival times, are included in a number of the previous studies.17 Kanda et al.12 investigated the prognostic influence of BTF on patients with stage II/III GC, but included only 250 patients, 57 who underwent BTF. Another issue to be considered is that most of the previous studies mainly included patients before the year 2010 and even before 2000, with a long study time period over 10 years. Remarkable advances in surgical techniques, peri-operative care, and adjuvant treatments for GC, over time, have resulted in obvious heterogeneity, which might have biased the results and conclusions.

As listed in Table 1 in the present study and in previous studies, the clinical and pathological characteristics between BTF and non-BTF patients were significantly different before matching. Some of these factors, such as tumor size, tumor location, and combined multi-organ resection, are well-known adverse predictors for OS and DFS after gastrectomy for GC. Meanwhile, some of these factors were also independent risk for peri-operative BTF, as listed in Table 2. Thus, the association between BTF and decreased long-term survival may be befuddled by other variables. Therefore, as the first study to our knowledge, we have investigated the putative impact of peri-operative BTF on the prognosis of patients who underwent radical gastrectomy with pathologically diagnosed stage II/III GC. We used PSM and multivariate Cox regression analysis to balance out differences in clinicopathological characteristics between BTF and non-BTF patients and to explore the influence of other potential risk factors. Our study verified that the influence of tumor- and operation-associated factors including advanced tumor stage and longer duration of surgery was significantly more important than the influence of BTF on oncological outcomes.

BTF was clearly shown to be linked to both a decrease in OS and DFS after univariate and multivariate analyses in the entire cohort before matching. However, because of the significant differences in prognostic factors between BTF and non-BTF patients, this conclusion should be carefully interpreted, and as shown in the present study may well be coincidental. PSM analysis is widely used in retrospective cohort studies to control for confounding biases, mimicking a randomized trial, with the assumption that all related confounders are controlled.21 As listed in Table 1, after matching, most of the important basic characteristics become comparable except for pre-operative hemoglobin levels and intra-operative blood loss, which were considered to be the main factors associated with BTF. These 2 factors were not used for enrolment for matching to avoid too many patients who received BTF being excluded because of a lack of matching. Further multivariate analysis identified that either pre-operative anemia (< hemoglobin 100 g/L) or intra-operative blood loss ≥ 300 mL were independent risk factor for poorer OS or DFS in the propensity matched cohort.

BTF was no longer significantly associated with poorer OS (P = 0.850) or DFS (P = 0.974) on univariate analysis in the propensity matched cohort. To adjust further for other misleading factors, multivariate Cox regression analyses with possible predictors (P ≤ 0.1 in the univariate analysis) were applied, and BTF was confirmed not to be an independent risk factor for DFS or OS (P = 0.552, P = 0.474, respectively). Therefore, the combined use of PSM and multivariate Cox regression analyses can offer statistical power to improve the reliability of our final conclusions. Thus, the negative association between BTF and long-term outcomes in the entire cohort is likely not associated with BTF itself but rather with the clinical circumstance requiring blood transfusions.

The same conflicting conclusions were drawn for hepatocellular carcinoma,22 rectal cancer,24 prostate cancer,25 and cholangiocarcinoma.26 BTF was confirmed not to be significantly associated with oncological outcomes by PSM analysis. The finding of these studies, that BTF is a surrogate marker for higher risk patients and does not influence long-term survival, could be theoretically confirmed by a randomized controlled trial. Whereas, a large sample-based observational analysis appears to be the best alternative to investigate the effects of BTF on oncological survival. PSM analysis provides researchers with the ability to balance all potential risk factors between two groups, thus mimicking a randomized controlled trial.27

Even though BTF was not identified to influence long-term survival in the present study, avoiding unnecessary BTF is of prime importance for a number of reasons. Excepting cost, the possible adverse effects of BTF are well known, such as immunomodulation, transfusion-transmitted diseases, and a higher risk of peri-operative morbidity and mortality.28,29 Various studies have revealed that a restrictive (hemoglobin level 70 or 80 g/L) red cell transfusion strategy was non-inferior to a liberal strategy in cardiac and hip surgical patients with respect to peri-operative morbidity and mortality.30‐32 But whether the results would be the same in patients who underwent gastrectomy has not been investigated, and there is also a lack of research on whether different BTF strategies have an impact on long-term survival.

It is worth pointing out that only stage III and longer operation time (≥ 240 min) were confirmed as independent risk factors for both decreased OS and DFS after radical gastrectomy for stage II/III GC. Whereas quite a few of well-known factors which significantly affect oncological outcomes of GC, such as depth of invasion, lymph node metastasis, and adjuvant chemotherapy, were not identified to be independently associated with long-term outcomes in the propensity score matched cohort.33,34 The possible explanation is that pTNM stage, which combines the depth of tumor invasion and lymph node metastasis, is identified as the most powerful indicator for predicting the prognosis. If we do not enroll pTNM stage into multivariable Cox regression, both of the depth of tumor invasion and lymph node metastasis were identified to be significantly associated with the prognosis (HR 2.309, 95% CI 1.356–3.931, P = 0.002; HR 2.343, 95% CI 1.436–3.824, P = 0.001). The reason for adjuvant chemotherapy is that patients with stage II GC seem less likely to receive adjuvant chemotherapy than those with stage III diseases, although the difference was not significant (29.8 vs 23.7%, P = 0.235). Thus, adjuvant chemotherapy seems a confounding factor in the association between tumor stage and prognosis, rather than an independent risk factor for prognosis in the present study. A longer operation time usually means that the operation is technically difficult, probably due to overweight, iatrogenic injury, extended lymphadenectomy, or combined multi-organ resection, which may affect the long-term survivals. But the results may change if the cutoff value of operation time was changed. Thus, the conclusion must be interpreted with caution. Additionally, due to insufficient data on immune functions and all of the transfused patients in the present study were performed non-irradiated packed red blood cells, whether the results were the same among patients who received irradiated red blood cells or whole blood needed further investigation.

Finally, although there have been several studies investigating the association between peri-operative BTF and the prognosis of patients who underwent gastrectomy for GC, the definition of peri-operative BTF and BTF protocol varied significantly among different studies. There was one study that included only patients who received BTF intra- and/or post-operatively,10 while the majority of the previous studies included patients who received BTF 1 or 2 weeks before surgery, and 1 or 2 weeks, even 1 month after surgery.12,14‐16 While in the present study, peri-operative BTF was defined as the transfusion of packed erythrocytes from the admission time to the day of discharge during hospitalization (usually 3–5 days before operation and 10–14 days thereafter). Although the exact time span is not fixed as previous studies, the BTF records during the present hospitalization is easy to get, accurate, and reliable. Given the varied definitions of peri-operative BTF and BTF protocols among different hospitals and doctors, the conclusions must be cited with caution, and an international multi-center study with larger sample size is necessary in the future.

There are several limitations of the present study including its retrospective nature and single-institution design. Second, the median follow-up time (33 months) was relatively short and the median OS and DFS in several subgroups could not be determined. Third, the pre-operative hemoglobin and intra-operative blood loss were unbalanced between the patients who were given BTF and those who were not in the propensity score matched cohort, which may affect the reliability of our conclusions. Fourth, although propensity score matching analysis has the advantage of reducing selective bias, it restricts the analysis to a relatively small proportion of the patients, thus dramatically increases the possibility of a type II error, limits the statistical power, and inflates the confidence intervals. Last but not the least, some patients in the present study received platelet or plasma transfusions, which might also affect the patients’ immune status or interact with BTF to influence the oncological outcomes;35,36 we did not investigate these potential associations.

The present study from a high-volume center in China has revealed that BTF is not significantly linked with OS and DFS for stage II/III GC after radical gastrectomy, by a combination of PSM and multivariate Cox regression analyses. Worse oncological outcomes are caused by the clinical circumstances requiring BTF, including a longer operation time and advanced tumor stage, and are not due to BTF per se.