Isoquercetin as an Adjunct Therapy in Patients With Kidney Cancer Receiving First-Line Sunitinib (QUASAR): Results of a Phase I Trial

Abstract

Sunitinib is the most commonly prescribed drug for advanced renal cell carcinoma in the first-line setting and has been associated with multiple adverse events related to its on–and off–target effects, including hand and foot syndrome and fatigue. It was hypothesized that sunitinib-induced fatigue may be related to off target inhibition of the AMPK enzyme, which results in impairment of energy-producing processes at a systemic level. Quercetin is a naturally occurring flavonol with established AMPK-stimulating activity. While clinical use of quercetin is limited by its poor bio-availability, quercetin-3-O-β-d-glucopyranoside, that is isoquercetin, has an improved pharmacokinetic profile. On the grounds of the in vitro stimulatory activity with respect to AMPk, we hypothesized that oral isoquercetin could improve fatigue in kidney cancer patients receiving sunitinib. Given the lack of data on the safety of isoquercetin given concomitantly with sunitinib, we conducted a phase I trial to assess the safety of GMP manufactured isoquercetin given at two dose levels (450 and 900 mg a day). In the 12-patient study cohort included in this study, isoquercetin was administered concomitantly with 50 mg sunitinib for a median 81 days (IQR, 75.5, 86.5). None of the 12 patients required isoquercetin suspension or isoquercetin dose reduction because of adverse events. No abnormalities in ECG, heart or lower limbs doppler ultrasound were detected. A statistically significant improvement was reported for the FACIT fatigue score (6.8 points; 95% CI: 2.8–10.8; p = 0.002) and for the FACIT Adverse Events score (18.9 points; 95% CI: 9.1–28.8; p < 0.001) after isoquercetin consumption vs. baseline. In this phase I trial, isoquercetin was remarkably safe, with a preliminary signal of activity in terms of improvement of sunitinib adverse events.

Potential Therapeutic Targets of Quercetin, a Plant Flavonol, and Its Role in the Therapy of Various Types of Cancer through the Modulation of Various Cell Signaling Pathways

“…It was observed that Qu-3- O -β- d -glucopyranoside has an enhanced pharmacokinetic report. On the grounds of the in vitro stimulatory activity, with respect to AMPk, oral administration of Qu could improve fatigue in kidney cancer patients receiving sunitinib [ 153 ]. Another combination drug therapy study conducted by Wei Li et al asserts that, since Qu and hyperoside (QH), in combination of a ratio of 1:1, have earlier demonstrated to prevent the growth of human leukemia cells; the same can be replicated by examining the anticancer activities of the same mixture in 786-O renal cancerous cells.…”

Anti-Inflammatory Diets and Fatigue

“…The flavonol quercetin, a yellow natural dyestuff in many fruits and herbs, has been investigated for its anti-inflammatory effects in animal models and different cell lines [70], as well as in humans [71]. The beneficial effect is mainly based on its adenosine monophosphate-activated protein kinase stimulating activity [72] which inhibits NF-κB and inflammatory pathways [73]. Animal models are contradictory in their results regarding the role of quercetin in preventing cancer-related pro-inflammatory levels and fatigue [74,75], and large-scale human trials are not yet available.…”

“…However, the effects did not last for the whole treatment period and it has to be considered that the interim observed improvements in fatigue might have resulted from the complete response to cancer treatment. On the other hand, an uncontrolled phase I trial revealed not only a safe daily supplementation of 450 mg or 900 mg isoquercetin for a median of 81 days (range 75.5–86.5) in 12 patients with kidney cancer receiving 50 mg sunitinib/day, but also a significant reduction in fatigue scores ( p = 0.002) [72]. However, inflammatory profiles were not examined and considering the uncontrolled study design, the results have yet to be verified in larger scale RCTs.…”

Kaempferol, Myricetin and Fisetin in Prostate and Bladder Cancer: A Systematic Review of the Literature

“…The attractiveness of these compounds as anti-cancer agents lies in multiple factors, including their availability on the market, low cost, low toxicity, low likelihood of pharmacological interactions as well as potential for synergism with anti-cancer medications. Our work group has reported the encouraging activity of isoquercetin against adverse events associated with sunitinib, including fatigue, hand and foot syndrome, rash in a small cohort of 12 patients with kidney cancer [24]. Furthermore, we reported an unusual complete response obtained with low dose oral cyclophosphamide and high doses of oral quercetin in an older patient with advanced urothelial carcinoma [82].…”

“…Among the several known flavonols, quercetin and its glycosylated form, isoquercetin represent the most studied compounds [23]. Isoquercetin has also been tested as a GMP medicinal product in prospective clinical trials as an adjunct therapy against sunitinib-induced fatigue by Buonerba et al [24] and as preventive measure against cancer-associated thrombosis by Zwicker et al [25]. Other less extensively studied-yet also promising-flavonols include kaempferol, fisetin and myricetin.…”