In this study, we evaluated the safety and effectiveness of Nuvastatic™ in improving fatigue in patients with stage I–IV solid tumors receiving chemotherapy. We enrolled 110 patients—54 receiving placebo and 56 receiving Nuvastatic™ 1000 mg. Demographic and baseline characteristics were generally balanced between the two groups. Nuvastatic™ intervention caused significant improvements in primary and secondary endpoints, which were tested per the hypothesis testing procedure, from baseline to the last visit compared with the placebo. Nuvastatic™ effectively reduced the mean BFI score, ECOG status, and VAS-F score. In the secondary endpoint, the Nuvastatic™ group showed significantly higher mean SF-36 QoL scores for physical functioning, physical limitation, emotional limitation, fatigue, and social function than the placebo group. The patient-reported improvement in QoL assessment following Nuvastatic™ treatment was substantiated by the low mean fatigue scores in the symptom indices (BFI and VAS-F) compared with the placebo. The complementary trend between QoL and fatigue scores supports previous findings, where the smallest difference in the mean QoL scores is clinically important and indicative of QoL improvement [16–18]. The efficacy of Nuvastatic™ in improving the fatigue status and enabling a better physical and social performance of patients was further substantiated with significantly low oxidative stress levels, as measured by the levels of the inflammatory marker F2-IsoP.
As an indicator of CRF severity, urinary F2-IsoP concentrations were significantly reduced in the Nuvastatic™ group at baseline and week 9; however, no significant changes were observed in the placebo group. This is a novel study to report F2-IsoP concentrations as a marker for CRF severity in clinical studies. Other studies have assessed inflammatory markers, (C-reactive protein, interleukin (IL)-1, IL-6, and tumor necrosis factor receptor type II) to evaluate CRF severity [19]. Our results conform with those of previous studies, associating high F2-IsoP concentrations with fatigue severity and low QoL in other disease settings [8–10]. Furthermore, cumulative evidence supports the role of effective antioxidant dosing in lowering F2-IsoP concentrations [23].
This study found that administering Nuvastatic™ 1000 mg thrice daily as an adjunct to chemotherapy is safe; to date, there have been no reports of severe adverse effects. Overall, ten patients (9.1%) experienced mild AEs (eight and two in the test and placebo groups, respectively; however, these events did not cause the withdrawal of the patients from the study or death. Hence, this study establishes the safety profile of Nuvastatic™ mainly in patients with solid stage I–IV tumors receiving chemotherapy, supporting this drug’s beneficial effects for fatigue and physical limitation.
The active compounds in Nuvastatic™, namely, rosmarinic acid, sinensetin, and eupatorin, possess strong antioxidant properties [24, 25]. Each compound alone or in combination is effective in reducing oxidative stress and inflammation [26]. Rosmarinic acid reduces seasonal allergy activity by inhibiting inflammatory response and radical scavenging, whereas eupatorin and sinensetin exert anti-inflammatory effects by inhibiting inflammatory receptors and enzymes and suppressing inflammatory gene expression [25, 27]. Rosmarinic acid also exerts anti-analgesic and anti-inflammatory properties [28]. Additionally, plant extracts containing high-rosmarinic acid content have been implicated in facilitating deep sleep [29].
Angiogenesis inhibition is an effective treatment for solid tumors and CRF [30]. C5OSEW5050ESA, which is the active compound in the Nuvastatic™ formulation, has antiangiogenic and immunomodulatory properties. It inhibits the production of vascular endothelial growth factor, epidermal growth factor, fibroblast growth factor, IL-2, IL-7, nerve growth factor β, transforming growth factor-α, and tumor necrosis factor-β. Additionally, C5OSEW5050ESA upregulates interferon α, β, and γ and granulocyte–macrophage colony-stimulating factor. Because these enzymes, receptors, and cytokines play critical roles in carcinogenesis, their modulation may help reduce disease burden and improve the QoL of cancer patients. These properties may have also contributed positively toward the anti-CRF properties of Nuvastatic™ that was observed in this study. Additionally, phytochemicals present in the Nuvastatic™ O. stamineus extract have pharmacological properties.
Overall, these previous studies support our hypothesis that Nuvastatic™ can effectively reduce fatigue and pain levels in cancer patients who have solid stage I–IV tumors. Patients receiving Nuvastatic™ also showed improved QoL, social–emotional state of mind, and physical ability in dealing with normal work compared with receiving placebo, starting from V3. This rapid response is of interest because of the ubiquity and enervating effects of CRF experienced by cancer patients, which have no specific treatments currently available on the market. Hence, the outcomes of this study and previous research propose Nuvastatic™ as an effective intervention for CRF.
According to our data, Nuvastatic™ has a potential clinical benefit in improving CRF for patients with various cancer types following the administration of different chemotherapy types. Thus, CRF is mediated by broadly expressed entities that are not tumor- or chemotherapy-type specific, e.g., reactive oxygen species (ROS). This study highlights the potential use of enhanced concentrations of urinary F2-IsoP, a product of ROS, as a surrogate marker for CRF severity.
Further research is warranted to investigate the mechanism of action (i.e., effect of Nuvastatic™ on different inflammatory mediators that can cause CRF) and the most beneficial and safest type and dosage of Nuvastatic™ in treating CRF in advanced cancer patients. We must also identify the patient subgroup by cancer type that will most likely benefit from Nuvastatic™ treatment, the effect of Nuvastatic™ resistance on CRF reduction, and possible occurrence of adverse effects following the long-term usage of Nuvastatic™.
This study has some limitations. First, it involves patients with various cancer types, mainly stages I–IV tumors, receiving a broad range of chemotherapy regimens, which presents a challenge to establish a cancer- and drug-specific baseline, given the small sample size; nonetheless, the ECOG score and other parameters as well as the chemotherapy regimen followed were generally equally distributed between both groups. This could be improved using a larger patient population undergoing a specific chemotherapy regimen and having the same cancer type. Second, there was a lack of further fatigue-associated endpoints (muscle pains, strength, QoL, and cognition). The difference in cancer types between both groups may contribute to the difference in the fatigue and QoL scores. Group differences in the F2-IsoP concentrations should also be mentioned, and as was done in this study, the monitoring of F2-IsoP concentrations should be continued even after baseline measurements. Hence, a larger study comparing fatigue scores between cancer types is needed. Third, we failed to assess the treatment duration required for Nuvastatic™ to reduce other fatigue-associated functional limitations (occupational impairment and costs of care issues).