Background
Prognostication of life expectancy is a significant clinical commitment for clinicians involved in oncology, especially in hospice-palliative care settings. Accurate estimates provide patients and families with a time frame in which to emotionally and financially prepare for the death [
1]. However, studies on survival prediction in terminally ill patients suggest that it is very difficult to make an accurate prognosis and even experienced palliative care physicians find such a prediction difficult [
2].
Patients with malignant tumors have higher oxidative stress (OS) by tumor growth itself and/or increased systemic inflammatory response [
3,
4]. OS is defined as a state in which the level of toxic reactive oxygen intermediates overcomes the endogenous antioxidant defenses. OS can therefore result from either excess production of free radicals or depletion of antioxidant defenses [
5]. Meanwhile, vitamin C is a well-known antioxidant that humans are unable to synthesize and must obtain from an exogenous source. Reductions in vitamin C intake are associated with illness, hospitalization, and institutionalization. A population-based cohort study with breast cancer patients demonstrated that women consuming the highest tertile of vitamin C were significantly more likely to survive compared to those in the lowest tertile of intake [
6]. Furthermore, a recent study reported that patients with low plasma levels of vitamin C have a significantly worse prognosis than patients with normal levels [
7].
While a few studies have shown a correlation between survival and either serum vitamin C level or OS in cancer patients, direct evidence for this association in terminally ill cancer patients is lacking. Therefore, we aimed primarily to determine the relationship between survival and serum vitamin C or OS level in terminally-ill cancer patients. In addition, even if not associated with survival, we investigated whether these specific laboratory findings were connected with performance status (PS).
Discussion
The idea of being able to prognosticate from the results of a simple blood test is very appealing to palliative care physicians. The need for a blood sample must also be weighed against the likely clinical advantage for the individual patient. Biologic parameters have not been as widely investigated as clinical parameters in terminally ill cancer patients [
12], and a more accurate evaluation of these variables in relation to prognosis is undoubtedly warranted.
To our knowledge, this is a rare study that investigated the clinical effectiveness of measuring serum vitamin C or OS in terminally ill cancer patients. In this study, the main findings were that: (i) these parameters had no prognostic significance; (ii) serum OS level was associated with PS of patients; and (iii) serum vitamin C level was not correlated with OS level.
It is well known that cancer patients are characterized by higher levels of OS markers and lower levels of serum vitamin C than healthy controls; there is a scarcity of literature addressing the association with survival of advanced cancer patients at the end of life [
13]. Mayland et al. [
7] reported that low plasma vitamin C concentrations were associated with shorter survival in terminally ill cancer patients. But those findings were not confirmed by multivariate analysis and they did not address the level of OS, which could be a predictor of cancer-specific survival [
14]. In the current study, we were unable to demonstrate prognostic significance of serum vitamin C or OS on survival. The lack of significance could be due to (i) true negative finding: these parameters are not helpful to discriminate the patients with a short survival, or (ii) false negative findings: small sample size or artificial cutoff value.
While several studies have shown that OS level was associated with the cancer patient’s PS [
15,
16], little work has been done in terminally ill cancer patients. The distressing symptoms experienced by cancer patients may be related to OS: these symptoms may also lead to the patients’ poor PS [
17]. Especially in the terminal stage, deranged energy metabolism, which may account for symptoms such as nausea/vomiting, anorexia and cachexia that cause malnutrition, could accelerate the production of free radicals. Additionally, a previous study reported that the OS levels decreased significantly after antioxidant treatment regardless of patient’s PS [
15], although these reductions might not lead to performance improvement [
17,
18]. Further well-controlled clinical trials are needed to clarify the clinical effect of intervention.
Based on the complex situation caused by an imbalance between OS and antioxidant ability, it is plausible that separate assessments of OS and antioxidant status do not provide sufficient information [
19]. For that reason we assessed both parameters, but could not find any correlation between them. With healthy adults, Block et al. [
20] found that serum vitamin C was inversely correlated with biomarkers of OS even after adjusting for other antioxidants. The antioxidant system counteracts OS constantly and prevents certain damage by scavenging reactive oxygen species [
21], but this balance may be limited to healthy subjects. As the disease progresses and death nears, OS levels escalate markedly without linear reduction of antioxidant capacity. Therefore, a higher OS level may have more influence on the outcome for terminal cancer patients than decreased antioxidant biomarkers. Two recent studies by Vera-Ramirez et al. with breast cancer patients back this up. In non-metastatic breast cancer patients, they demonstrated that both antioxidant capacity and OS biomarkers had significant association with survival rate [
22]. In contrast, in a metastatic setting with the same protocol, only OS parameters significantly influenced the survival rates of the patients [
14].
The current study contains some limitations that should be acknowledged. First, this sample of patients is too small. Large-scale studies are needed to confirm our findings, because short survival time is unavoidable when dealing with subjects in a hospice setting. Second, by using a single measurement, we have likely underestimated the association of serum vitamin C level and OS status with survival. Third, we only adjusted for confounders statistically and could not exclude acute inflammatory conditions or anti-inflammatory medication users, which can affect OS [
23]. However, terminally ill cancer patients are very susceptible to infection [
24], and they have also taken multiple drugs due to a wide variety of symptoms and associated comorbid conditions [
25]. Finally, some symptoms such as anorexia, dysphagia and dyspea on exertion were not evaluated by a validated symptom assessment tool.
Competing interests
CHY is the chairperson of the Korean Association for Vitamin Research. All authors have no potential conflicts of interest concerning this article.
Authors’ contributions
CHY, YSC, and ICH designed study. CHY, YSC and ICH wrote the manuscript. YSC, SHL and ICH conducted study and collected the data. AHY and ICH analysed the data. CHY, YSC and ICH interpreted the data. All authors read and approved the final manuscript.