Background
Anemia is a condition that develops when whole blood lacks sufficient healthy red blood cells or hemoglobin (Hb), an oxygen-carrying protein within red blood cells. Cancer-associated anemia is one of the most common paraneoplastic syndromes during cancer progression or treatment and is prevalent in 30% to 90% of cancer patients [
1]. Although anemia incidence varies with cancer types, stages and patient characteristics, it has been estimated that over 40% of all cancer patients are anemic at diagnosis, a rate that increases by an additional 40% after chemotherapy or radiation therapy treatments [
1‐
4]. Because cancer-associated anemia has been documented as an adverse prognostic factor as well as predictor of treatment response, [
5,
6] evaluations of anemia and anti-anemia treatments have significant clinical implications.
The diagnosis and treatment of anemia are influenced by various factors, such as hemorrhage, hemolysis, nutritional deficiency, hereditary disease, renal dysfunction, and systemic chemotherapy or radiation therapy [
7,
8]. Since clinical symptoms of anemia start slowly, Hb level is currently the most important predictor in guiding anemia evaluation and treatment, regardless of the underlying causes [
3]. Correction of cancer-associated anemia is usually achieved by blood transfusion with packed red blood cells (PRBCs) or erythropoiesis-stimulating agents (ESAs). However, considerable controversy regarding the safety and restrictions on the correction modality of cancer-associated anemia has been recently reported. For instance, several recent meta-analysis studies reported that ESA administrations, while reducing the incidence of clinically defined anemia, may confer an adverse survival to patients exhibiting a large change in Hb levels during treatment [
9‐
12]. In comparison, other studies did not identify such significant effects of ESA use on patient mortality [
13,
14]. These studies suggested the complexity in the diagnosis and tailored treatment of anemia in the context of broad variations in Hb levels.
Given the wide variations in Hb level among cancer patients and even healthy individuals, it is impractical to define a clinically universal “normal” Hb value. Moreover, during anti-anemia treatment in clinics, it remains controversial as to the time to start initial treatment and the targeted range of Hb levels. For example, the baseline Hb values that trigger ESA treatment for patients with cancer- or therapy-induced anemia range from 8 to 11 g/dL under different practice guidelines [
3,
15‐
18]. The newly updated National Comprehensive Cancer Network (NCCN) guideline suggests that in non-anemic patients with a high baseline Hb level, a drop of 2 g/dL or more should be evaluated for the presence of anemia [
3]. This raises the question whether a change in Hb levels during follow-up or treatment, regardless of baseline or single time point Hb levels, can directly predict patient prognosis. In the present study, we sought to utilize a large hospital-based cancer patient cohort to comprehensively evaluate post-diagnosis Hb change (∆Hb) as a predictor of overall survival in patients with lung, breast, colorectal, or liver cancer, four of the most common causes of cancer-related deaths. To the best of our knowledge, this is the first population-based epidemiological study that evaluates Hb changes (either an increase or a decrease) in association with cancer patient prognosis.
Discussion
In this study, we evaluated the association between ∆Hb measured within six months after cancer diagnosis and the overall survival of a large population of 6675 patients of four different solid tumors. Our data indicated that Hb changes after diagnosis had an adverse effect on the patient survival. The effect was in a dose-dependent manner and could persist over a long period after diagnosis. In addition, Hb changes seemed to also modulate the elevated risk of death associated with clinically defined anemia in cancer patients.
Many factors may induce anemia in cancer patients, such as bleeding, hemolysis, renal insufficiency, insufficient erythropoiesis caused by chronic inflammatory cytokines during carcinogenesis or myelosuppressive chemotherapy treatments, and nutrition deficiency [
4,
8,
22,
23]. In the current clinical setting, regardless of the different underlying causes of anemia, the evaluation of the severity of anemia mostly depends on the level of baseline Hb. However, wide variations of Hb levels among cancer patients, or even the general population, have been extensively reported, making it difficult to diagnose anemia solely based on a single measurement of Hb level at baseline. The newest updated NCCN guideline suggested that a drop of as little as 2 g/dL in Hb level, even in non-anemic patients with a high baseline Hb level, is an alarming indicator for the presence of anemia [
3,
24‐
26]. Nonetheless, as yet there has been no report systemically evaluating the role of post-diagnosis change of Hb level in predicting cancer patient survival. To the best of our knowledge, this is the first population-based study to assess the association between Hb change and overall patient survival in multiple cancers. Consistent with the suggestions from the NCCN guideline, our findings indicated that changes in Hb levels in cancer patients after diagnosis should be monitored and taken into consideration in the evaluation and determination of their treatment plans.
We noticed that both decreased and increased Hb levels were associated with a significantly poorer survival (Table
2 and Figure
2). The observation for decreased Hb was not surprising since at least a portion of Hb decrease might be accounted for by cancer- or treatment-related anemia. However, it was interesting to notice that an increase in Hb level, which usually indicates the alleviation of anemia, also conferred an increased risk of death. Moreover, in the analyses for four cancers combined, as well as individual lung cancer and breast cancer, patients with an increased Hb level showed an even more prominent adverse survival compared to those with a decreased Hb, with an HR of 1.53 versus 1.35, 1.59 versus 1.25, and 1.65 versus 1.45, respectively (Table
2). The mechanisms underlying these observations remain elusive. One potential explanation might be the use of anti-anemia medications such as ESAs or PBRC. There have been several recent studies highlighting the controversial clinical benefits and risks of using ESAs and/or PBRC to help alleviate cancer- or therapy-related anemia [
9,
11,
12,
27‐
30]. Some of these studies reported that overdose or over-duration in the treatment of anemia might result in elevated rate of patient death [
9‐
12]. Our results indicated that a significant increase in Hb level after cancer diagnosis was associated with adverse patient survival, substantiating these previous reports using a population-based epidemiological approach. Nonetheless, it should be noted that although these observations are clinically plausible, they lack supports from solid clinical evidence since we currently do not have complete anemia treatment information from our chart review-derived database. Future studies with a more comprehensive collection of anemia diagnosis and treatment data are warranted to validate these hypotheses.
Clinically diagnosed anemia has been associated with unfavorable patient prognosis [
31]. However, the current treatment of anemia does not always result in improved patient survival, suggesting additional criteria are needed in determining and monitoring the effects of anti-anemia therapies [
32]. In the present study, we found that the significantly increased risk of death conferred by anemia was evident in those patients with a small Hb change of less than 4 g/dL, but not in those with an Hb change of more than 4 g/dL (Figure
4). These results indicated that post-diagnosis Hb changes may help improve the decision making process of anemia correction treatment in clinical settings. Specifically, it raised the question whether anti-anemia medications should continuously be administered to patients with a relatively large change in Hb level in a short period of time. Nonetheless, since our analysis did not include anti-anemia treatments which could significantly confound the results, independent studies with more complete anti-anemia treatment data are needed to validate these findings with regard to their clinical relevance.
Although anemia is a ubiquitous comorbidity in cancer patients, its prevalence in different cancer types vary widely, ranging from 30% to 90% [
1]. A recent large population-based study reported that CRC patients had the highest incidence of anemia at diagnosis among all solid tumors, whereas there was no apparent Hb change in CRC patients within five years before diagnosis [
33]. In the present study, post-diagnosis Hb changes in CRC patients were most significantly associated with overall survival among the four cancer types, as evidenced by the 100% validations with
P<0.01 in bootstrap resampling in the analyses of both |∆Hb| and ∆Hb levels (Table
2). In comparison, for breast cancer, no significant results were validated for the association between ∆Hb and patient survival. It remains to be determined as to whether gender played a role in these observations. We compared the |∆Hb| of breast cancer patients to that of female patients of the other three cancers and found that breast cancer patients had the smallest Hb changes among all female cancer patients (
P<0.001 for all three comparisons, Figure
1). These differences were likely due to cancer type instead of gender status, because such significant differences were not identified between male and female patients in the other three cancers (
P= 0.056, 0.096 and 0.850 for lung, colorectal and liver cancers, respectively, Figure
1). Although the mechanism underlying these cancer type-specific findings remains to be investigated, these data suggest that the use of Hb changes in anemia management and patient prognostication should be individually assessed for different cancer types.
There are several strengths in this study. We had a large population of 6675 patients from a single institute and our conclusions were consistent among four different cancer types. The study was focused on the extensive analysis of a single variable and, thus, did not have the multiple comparison issue. The findings were highly statistically significant in both the Cox regression and the log rank analyses with strict internal validations using bootstrap resampling, indicating that the possibility of false positive findings is unlikely. Meanwhile, our study also has limitations. Because this study used archived clinical data obtained from chart review instead of prospectively collected data, many cancer type-specific data did not have complete and/or standardized records in medical charts and thus had a relatively large percentage of missing values. In addition, important confounding variables such as anti-anemia modalities and treatment toxicities were not complete in our database and thus not adjusted in the multivariate analyses. Therefore, our data, although highly statistically significant and biologically plausible, need to be further substantiated in more rigorous studies using large independent and prospective populations with a more comprehensive collection of relevant confounding variables.
Competing interests
The authors declare that they have no competing interests
Authors’ contribution
SW conducted data collection, study design and manuscript writing. YL conducted data analysis. RM contributed to study design and manuscript writing. BL conducted data analysis and manuscript writing. JP contributed to study design and manuscript writing. AB contributed to study design and manuscript writing. GC contributed to study design, data analysis, and manuscript writing. JX contributed to study design and manuscript writing. HY conducted data collection, study design, data analysis, and manuscript writing. All authors read and approved the final manuscript.