Correction of anemia in patients who are receiving systemic chemotherapy has important clinical value, as anemia negatively impacts the patient’s quality of life and compliance of treatment in the oncology clinic. In this retrospective study, we showed that the pattern of anemia management in colorectal cancer patients receiving chemotherapy was significantly changed after implementation of the PBM program in oncology practice. The number of patients receiving RBC transfusion as well as the amount of transfused RBC decreased after the specific guideline for cancer patients was implemented. Instead, iron supplementation was significantly increased to minimize blood transfusions. As a result, the mean hemoglobin levels increased gradually over the study period, while the baseline clinical characteristics of patients remained consistent. Of note, we also observed that blood transfusion was a significant unfavourable factor influencing OS along with the number of metastatic sites at diagnosis in advanced colorectal cancer patients.
In patients with anemia receiving myelosuppressive chemotherapy for advanced cancer, it is recommended to correct anemia with iron replacement and/or ESA to reduce transfusion [7, 8]. However, blood transfusion has also been frequently used in clinical practice alone or in combination with pharmaceutical measures. Many studies showed that perioperative blood transfusion in early stage cancer patients had a negative effect both on short-term surgical outcome and long-term prognosis of patients [18–21]. Most of all, colon cancer was the prototype of disease that was proven the relevance of transfusion and clinical outcome [22, 23]. The negative impact of blood transfusion was documented in multiple cancer types after extended follow-up investigations [24, 25], supporting restrictive transfusion in early stage cancer patients. However, the prognostic impact of transfusion in advanced cancer patients had not been sufficiently investigated. Patients with malignancy in the gastrointestinal tract are more likely to have anemia at the time of cancer diagnosis because of chronic blood loss, insufficient food intake, or chronic inflammatory condition. Moreover, anemia is aggravated with repeated cycles of chemotherapy. In the oncology clinic, however, correction of anemia is not a priority issue compared with the choice of treatment, management of side effects from chemotherapy, and pain control. In this study, patients who were transfused using packed RBC showed an inferior survival time irrespective of chemotherapy or initial tumour burden.
In the current analysis, blood transfusion was required in 20% of the patients (175 out of 871). Patients who required at least one unit of transfusion were characterized by more metastatic sites at diagnosis (more than 2 sites, 53 of 175 [30.3%] vs. 89 of 696 [12.8%]; p < 0.001) and more chemotherapy regimens over the lifetime (more than 2 courses, 75 of 175 [42.8%] vs. 99 of 696 [14.2%]; p < 0.001) (Supplementary Table 1). The increased probability of transfusion in patients with a high tumour burden could be explained by the fact that advanced cancer induces functional iron deficiency mediated by inflammatory mediators; hepcidin [26–29]. Thus, standard oral iron supplementation or ESA might not be effective for this patient group as in patients with benign conditions. Nevertheless, considering the limited therapeutic options for advanced colorectal cancer patients, better supportive care like restricting transfusion for anemia correction might be a valuable strategy to improve clinical outcome.
There are several well-known adverse events from blood transfusion, including blood-born infections, hemolytic reactions, transfusion-related acute lung injury (TRALI), and transfusion-related immunomodulation (TRIM) . TRIM is one of the major mechanisms underlying the negative impact of blood transfusion on clinical outcome in cancer patients. TRIM is mediated by residual leukocytes, apoptotic cells, and microparticles in blood components. Upon transfusion, the components of transfusion can modify immune functions, including decreasing the number of lymphocytes, CD4 cells, the CD4/CD8 T-cell ratio, NK cells and the lymphocyte response to mitogens. These effects might contribute to cancer growth and dissemination by compromising immune surveillance [31, 32]. The prognostic impact on patients receiving immune checkpoint inhibitors is not known. Indeed, there is sufficient clinical evidence to support the practice of restrictive transfusion and proactive correction of anemia in both early and advanced stage cancer patients.
Implementation of PBM at the institutional level is usually challenging, especially for high volume clinical settings like oncology clinics. The recognition of the potential hazards of blood transfusion and change in practice by young doctors who are responsible for primary care takes time. Good availability and low cost of transfusion were additional hurdles in building up the new culture in Korea. With institutional level educational programs and continuous feedback to faculty physicians, the use of blood transfusion dramatically decreased and the mean hemoglobin level in patients significantly increased in a short period. Moreover, the increased awareness of anemia by the treatment team was reflected by the increase in iron replacement. For the continuity of care pattern in anemia, cancer patient-specific guidelines were established and shared with rotating residents. Encouraged by the results from this study, a new practice of attentive care of anemia with restrictive transfusion is now the standard of care for all cancer types in our institution.
There are several limitations in our study. First, this is a retrospective study, and thus the prognosis of the patients might be inherently affected by unrecognized confounding variables. In oncology patients, the prognosis of patients is usually improved with the implementation of new agents and better supportive care. To investigate the prognostic impact of anemia correction, we selected metastatic colorectal cancer, as the standard of care has not significantly changed over recent years. Second, the results presented here are based on a single cancer type from a single institutional experience. Thus, the value of restrictive transfusion should be further evaluated in other cancer types and the clinical context in a multicentre or national database setting. Despite these limitations, we demonstrated that the implementation of restrictive transfusion by the implementation of PBM program were feasible to change practice patterns. Through these changes, we observed many valuable benefits in the oncology clinic, not only saving the costs of blood transfusion and reducing the burden of time-consuming and high-risk medical practice of caregivers, but also improving patient prognosis.
In conclusion, allogenic blood transfusion is an independent adverse prognostic factor in patients receiving chemotherapy for advanced colorectal cancer. Increased awareness of anemia and proactive use of medicinal strategies should be considered rather than transfusion for better prognosis of these patients.