Anemia is a common condition in the treatment process of cancer patients. The aim of this study is to detect lung cancer cases who received red blood cell transfusion due to anemia and to evaluate the results of transfusion-related patients.
Tumor‑associated anemia may occur in lung cancer patients may occur due to tumoral factors and tumor treatment-related factors. Chemotherapy-induced anemia (CIA) often develops in patients with cancer who are treated with myelosuppressive chemotherapy (4, 5, 6). On the other hand, it has been shown that when diagnosed with cancer, patients already have a significant risk of anemia, almost five times that of healthy people.
In our study, the data of 405 patients were scanned and 184 of these patients were detected as anemia (45.4%), 96 (23.7%) of all patients were with transfused red blood cells (RBC). According to the latest current guidelines, RBC transfusion should not be performed according to a certain “threshold value” or “trigger point”. The NCCN panel view draws attention to 3 important points; 1. Observation and periodic reassessment should be performed in asymptomatic patients without serious comorbidities. 2. Transfusion may be considered in patients receiving high-risk intensive chemotherapy and radiotherapy if there is a progressive decrease in Hb level, or in asymptomatic patients with comorbidities (cardiac disease, chronic pulmonary disease, cerebral vascular disease). 3. Transfusion should be applied in symptomatic patients (such as tachycardia, tachypnea, chest pain, exercise dyspnea, syncope). The onset, severity, and duration of anemia, as well as other factors affecting tissue oxygen delivery, are related to the clinical manifestations of anemia. Adaptation to the process in chronic anemias depends on heightened cardiac output, increased coronary flow, altered blood viscosity, oxygen consumption and extraction. The decision to correct anemia mainly depends on the individual characteristics of the patients, the severity of the anemia, the severity of comorbidities, and the clinical judgment of the physician (3).
In newly diagnosed cancer patients; Kenar et al. evaluated that metastatic disease, deficiencies such as iron, B12 and folate, gastrointestinal cancer, and a history of previous tumor surgery are possible risk factors (7). Direct infiltration of the bone marrow by cancer cells, reduction of RBC production by causing iron sequestration of cancer cells and shortening its life, chronic blood loss from tumoral areas, deterioration in oral intake and deterioration in the coagulation system can be evaluated as the causes of anemia seen in patients with cancer. All these reasons are mechanisms that increase proportionally with cancer weight (8, 9, 10).
The main purpose of RBC transfusion is to increase the oxygen carrying capacity to provide tissue oxygenation. In 2016, the American Association of Blood Banks made several recommendations suggesting that the threshold values of 7 g/dL Hb in hospitalized and hemodynamically stable patients, and 8 g/dL Hb levels in patients with orthopedic, cardiac surgery or known cardiovascular disease require transfusions (11). However, this recommendation did not include cancer patients. NCCN panelists state that a single value cannot be determined for all patients in the transfusion decision, and this decision should be made according to the individual risk/benefit ratios for the patient. In our study, the patients with an average value of 8.76 ± 0.78 Hb received transfusions based on not only the clinical assessment but also the finding that cardiac disease (36.8%) was the most common comorbidity.
In several reports, the mean Hb level was 9 g/dL, 9.5 g/dL, 9.7 g/dL before starting iron supplementation, transfusion or ESA use in cancer patients (12, 13, 14). Rather than a specific absolute value, studies have identified anemia symptoms as an important clinical indicator in the decision to transfusion, in contrast to non-cancer anemia states (15). In general, fatigue is not a major indication for transfusion other than cancer. In our study, 55 (13.6%) of 405 patients diagnosed with lung cancer died within a 24-month period. It is determined that while 38.2% of these patients (median 3.1 ± 3.0 units) were transfused, 21.4% (mean 2.81 ± 2.24 units) of 350 surviving patients were blood transfused (p=0.011). It was observed that 24-month mortality increased with blood transfusion. However, there was not a dose-dependent association between the amount of blood transfusions and survival outcomes of patients with lung cancer. There are few studies examining transfusion outcomes during routine chemotherapy in lung cancer patients. In a meta-analysis including 12,175 patients with lung cancer and 23 studies, it is found that blood transfusions were associated with decreased survival. However, only 1 of these studies evaluated transfusions during chemotherapy and perioperative transfusion results were evaluated in other patients (16). In the study of Sakin et al., similar to our results in this study, red blood cell transfusion was significantly associated with earlier progression and shorter survival. This study is important because it is the first study that evaluates transfusion outcomes in metastatic NSCLC patients. In this study, 87 patients who received blood transfusion were included and patients with small cell lung cancer and non-metastatic were not included. (17). In our study, there were 96 patients in the transfusion group and the results of all patients who received chemotherapy with the diagnosis of lung cancer were evaluated. Aoe et al. reported that regardless of the need for transfusion, survival was significantly shorter in 298 patients with anemia (median survival time (MST): 7.5 months) compared to 313 patients without anemia (MST: 11.8 months, P<0.0001) (18). As found in our study, there may be several possible reasons for more frequent blood transfusions in non-surviving patients; one of these can be explained as the fact that many chemotherapy agents cause myelosuppression and lead to anemia, and severe cancer patients are exposed to a longer and high-dose chemotherapy burden. In addition, the initial stages of non-survival patients in our study were more advanced and this may increase the need for blood transfusions in accordance with the anemia hypotheses. Another reason is the higher incidence of infectious complications, as determined in our study with frequent blood transfusions. In our study, the rate of infection requiring antibiotic use was 68.8% in the transfused group, while this rate was 35.3% in the non-transfused group. (p<0.001). In addition, the primary disease progression rate was found to be significantly higher in the infected group (67.4%) and this may have contributed to the increased mortality rates in the high group with transfusion frequency. The incidence of sepsis due to bacterial infections, which is one of the undesirable transfusion-related complications, is reported as less than 10 per year (19, 20). In a randomized controlled trial with 31 RCTs and 12587 patients, restrictive transfusion strategy was suggested and for nosocomial infections, there was a significant higher risk of infection among patients receiving fresher RBCs (21). On the other hand, recognition of the immunosuppression caused by frequent transfusions for cancer patients has raised concerns that blood transfusions may increase the risk of cancer recurrence, particularly after curative surgery (22). Over the past four decades, it has been estimated that blood transfusions cause cancer progression by reducing the immunity of patients. (23). Primer disease progression, which is an important prognostic indicator in lung cancer patients, was observed more frequently in patients who underwent transplantation in our study. Our results are important because they are one of the latest and rare data on transfusion in patients with lung cancer receiving chemotherapy. In fact, although the life-threatening risk is lower, the most common nonhemolytic transfusion reactions associated with RBC transfusion are expected. Hemolytic reactions, febrile reactions, lung damage, transfusion associated circulatory overload can be counted as other possible complications, but since our study was retrospective, these data could not be clearly reached in our patients.
One of our interests in our study was whether there was a delay in treatment in patients due to anemia. The chemotherapy of a small number of our patients (18 patients 4.4%) was delayed until after replacement or anemia treatment was arranged due to anemia, but this did not cause any difference in disease progression or mortality.
A. Tiotiu et al. rated the frequency of chemotherapy-induced anemia (CIA) in lung cancer and emphasized the impact on patients’ quality of life. They stated that maintaining a normal Hb level is important in improving the quality of life of these patients and recommended reducing the number of blood transfusions and initiating treatment with ESA (Erythropoietin Stimulating Agents) in symptomatic patients. They recommended that it should be used at the lowest effective dose and sharing the results with patients to avoid from increased risk of thromboembolism, accelerated tumor progression, decreased survival, and major cardiovascular adverse reactions and blood transfusion (24). ESAs stimulate erythropoiesis in patients with low Hb levels, but their effects appear weeks later, and an Hb increase of 1 g/dL was observed in only 65% of patients (25). The current guideline recommends that ESAs should not be used in cancer patients who are not receiving myelosuppressive therapy. Except the patients requiring blood transfusion and those in palliative care, the NCCN panelists do not recommend routine ESA treatment to increase Hb levels (3). ESA was not applied to any of the patients in our study. In the data of our study, in parallel with the data of our country, the most common cancer type was determined as SCC (22.2%) and no difference was observed in the need for blood transfusion according to cancer types and stages.
The limitations of our study can be listed as follows; 1. Since our study was planned retrospectively, patients who received immunotherapy were not included. 2. The effects of radiotherapy applied to patients have not been examined. 3. While detecting infections requiring antibiotics, data loss may happen because the focus of infection in some patients cannot be fully learned from retrospective records. Only pneumonia and upper respiratory tract infection data were included. 4.The assessments of iron stores ore iron treatments were not recorded. 5. Complications associated with transfusion therapy were not recorded.
As a result of our study, it was determined that red blood cell transfusions due to anemia during the disease in lung cancer patients who underwent chemotherapy, adversely affected survival and disease progression. Although the exact mechanism is not known, it is thought that transfusion-related immunomodulatory effects are effective on this result. We intend that our study will contribute to the literature as one of the few studies in the literature in this isolated patient group.