Proof of Concept in a Case Study of Glioblastoma Multiforme Successfully Treated with IV Quercetin in Combination with Leading Edge Gamma Knife and Standard Treatments ()
1. Introduction
According to the original study the Stupp protocol comprises:
• Radiotherapy
➢ total 60 Gy
➢ 2 Gy per daily fraction (Monday to Friday) over 6 weeks
• Temozolomide
➢ during radiotherapy: 75 mg per square meter of body-surface area per day, 7 days per week
➢ post-radiotherapy (adjuvant): six cycles consisting of 150 - 200 mg per square meter for 5 days during each 28-day cycle
Here are characteristic features of multifocal disease, which accounts for about 13 percent of cases:
• In one retrospective study [2] , researchers reviewed records of 368 newly diagnosed patients with GBM and identified 47 patients with multifocal tumors.
• Tumor progression was defined as increased enhancement on the 2- to 3-month postradiation magnetic resonance imaging scan vs the immediate postoperative scan, together with clinical decline.
• Factors leading to the worst median survival duration were age (>65 years), partial resection or biopsy, and low KPS (≤70) within the multifocal group.
• The median survival duration of older patients with multifocal disease (age > 65 years) was 4 months vs 12 months in younger patients (P = 0.0007).
• Patients with multifocal disease who underwent biopsy or partial resection had a median survival time of 5 months vs the 14-month median survival time seen in patients who underwent gross total or near-gross total resection (P = 0.04).
• Patients with multifocal disease with low KPS (<70) had a median survival duration of 3 months vs patients with high KPS (>70) who survived for 9 months (P = 0.04).
• Survival rates at 2 years were 4.3% for patients with multifocal disease and 29.0% for the unifocal cohort.
• Additionally, newly diagnosed patients with multifocal disease had an almost 2-fold increase in the hazard of death vs patients with solitary GBM (hazard ratio, 1.8; 95% CI, 1.1 - 3.1; P = 0.02).
• There were no significant differences in expression profile of any of the molecular markers between the multifocal and solitary GBM groups.
Quercetin has been studied extensively in variety of tumor types over decades. For a while it has been used in the form of IV in phase I and II trials with good safety and efficacy profile in cancer and other conditions including cardiovascular disease. Recently it has become a focus of interest, in treatment of Glioblastoma along with different forms of radiation and chemotherapy. Mechanisms of action in Glioblastoma have been identified both as independent as well as synergistic. Targets include HSP27 and COX2, a dual inhibition found in both in vitro and in vivo model [3] - [18] .
Quercetin also has been studied by our scientific collaboration with M D Anderson, in 3 dimensional cell culture model and has shown inhibitory effect on cell migration and glioblastoma spheroid viability (Figure 2).
Gamma Knife through leading edge technique showed improved outcome in a large subset of patients with Glioblastoma, due to its antimigratory effect [19] .
The rationale of combination therapy relies on the fact that theoretically, the combinational therapy enhances the inhibition on cellular migration and the application of gamma knife could increase the penetration of IV Quercetin in the blood brain barrier. The limiting factor is the bioavailability and the requirement for frequent treatments.
2. Methods and Materials
Quercretin was compounded under sterile conditions at FDA approved facility, and passed required testings for IV injection, further injected intravenously in the dose of 500 mg per treatment. Patient was educated about the therapy and appropriate consent forms obtained. Further she received the IV therapy through her central line at rate of 4 ml per minute, on daily basis per protocol.
Patient was a 70 years old white female (who worked as an accountant with no known exposure to carcinogens, or verifiable family history of cancer),diagnosed with multifocal glioblastoma multiforme in 2/24/17 in right frontal lobe, perisylvian area as well as anterior limb of internal capsule extending to right caudaual head and right frontal white matter, status post MRI guided stereotactic frontal lobe craniotomy on 3/6/17, and further Treatment with leading edge gamma knife radiotherapy and Temodar at 75 mg/m2 started on 2/24/17 and completed on 5/19/17. She had completed 35 sessions of radiation and further leading gamma knife directed by Dr Chris Duma at Hoag Hospital, and IV Quercetin started on 6/2/17. She also had a history of DVT in March that is currently treated with Eliquis. KPS was less than 70.
She was referred to us for evaluation and treatment on 5/31/17. Initial presentation was fatigue and inability to walk due to ataxia and disrupted gait. Physical examination revealed right foot drop and balance deficiency in walking and coordination.
Her labs indicated positive Circulating tumor cells (CTC) measured by PCR through Biofocus Lab on 6/16/17. Her tumor molecular profiling showed positive CIC, ATRX, TP53, PTEN and MGMT. Her pathology had shown a proliferative index (Ki67) of 90 percent.
This patient suffered from the worse prognostic markers for Glioblastoma, including Ki 67 of 90 percent (more than 22 percent, as cut off) as well as presence of CTC. Both markers are predictive of outcome [20] [21] .
She received 10 IV treatments completed on 6/20/17. All symptoms improved, including ability to walk and her requirement for steroids. Her physical examination post therapy showed improved balance and coordination. Her brain MRI on 6/20/17 showed no progression of disease and no new findings were reported. Post surgical findings were stable. Her ECOG score was reduced two points at this time. She was off Decadron, starting (5/31/17).
She was asymptomatic post treatment, except some heavy left foot (slight drop) otherwise her neurological symptoms have all recovered, including left hand disco-ordination.
By 8/15/17, she had received 28 treatments, where the notes indicate that she was walking better and was more stable, no difficulty with her balance noticed. Her brain MRI on 8/24/17 showed stable.
On 7/27/17 she had repeated circulating tumor cells (CTC) analysis which showed response to the IV Quercetin with reduction of the ERBB and Kit markers (please see Figure 1/biofocus1). Further on 10/6/17, she had third sample which showed complete resolution of all circulating tumor cells. (Please see Figure 2/biofocus2).
She underwent at least three brain MRIs post therapy, while under our care. (6/20, 7/6/17 8/24/17) Her brain multisequence imaging/MRI on 6/20/17 showed
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Figure 1. Title is “Circulating tumor cells”.
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Figure 2. Title is “Glioblastoma spheroid viability assay”.
positive response to the therapy, and that her necrotic tumor was decreased in size. Maximal dimension of the post surgical cavity had decreased from 4 to 3.7 cm. Further MRIs continued to show post surgical irregular dominant enhancements and patchy right periventricular satellite enhancements in frontal horn, all stable. Restricted diffusion in right centrum semiovale white matter was contributed to cellular non enhancing tumor.
Her last treatment was provided on 11/3/17. In our experience the therapy was feasible and well tolerated, that said the limiting factor was the requirement for frequent office visits for infusions.
Patient passed away from opportunistic infection and sepsis on 12/9/17, where her disease had regressed in our findings. She lived twice as her expected disease biological prognosis.
3. Discussion
Despite the significant recent efforts in research and drug development aimed at treatment of advanced Glioblastoma, yet the prognosis of the disease is grave. Significant biological barriers are blamed for the failure of therapies, including radiation at it’s the best technologies. Cellular migration seems to be a key element responsible for the progressive nature of this disease. Further enhanced drug delivery techniques are also being investigated including nano technology to increase the bioavailability of the antineoplastic agents. Application of gamma knife is documented to increase this penetration. By application of antimigratory agent Quercetin alone or in combination with radiation and chemotherapy, we have shown increased cellular apoptosis, inhibition of angiogenesis and further tumor necrosis and here we believe such therapy has provided a safe and effective measure in improving patient quality of life and survival.
4. Conclusion
Administration of IV quercetin in combination with leading edge gamma knife and STUPP protocol is feasible and in this case provided improved response and quality of life. Patient passed her expected survival. Further studies are required to investigate such combinational approach using Quercetin as an orphan drug designated for treatment of Glioblastoma multiforme.