Approximately 40–50% of glioblastomas (GBM) overexpress epidermal growth factor receptor (EGFR). Erlotinib is a specific and potent EGFR tyrosine kinase inhibitor active against refractory GBM. ...Patients with non-small cell lung cancer and ≥grade 2 erlotinib-induced rash have improved survival. This phase 2 study assessed the efficacy and safety of concurrent radiation therapy (RT) and temozolomide with pharmacodynamic dose escalation of erlotinib in patients with newly diagnosed GBM. Patients received RT 60 Gy in 30 fractions with concurrent temozolomide 75 mg/m
2
/day × 42 days, followed in four weeks by temozolomide 150–200 mg/m
2
/day × 5, every 28 days for 12 cycles. Patients received erlotinib, 50 mg/day and increased by 50 mg/day every 2 weeks until the occurrence of grade 2 rash or to a maximum dose of 150 mg/day, from day 1 until disease progression. Twenty-seven patients were treated in this study. Twenty-two (81%) patients came off study for progressive disease (18 67%) or adverse events (4 15%). Eighteen patients (67%) have died. Median progression-free survival was 2.8 months, and the median overall survival was 8.6 months. Five patients remain on study with a median follow-up of 16 months. Grade 3/4 toxicities included thrombocytopenia, anemia, lymphopenia, fatigue, and febrile neutropenia. There were four deaths on study, three definitely treatment-related; therefore, the trial was terminated after accrual of 27 of 30 planned patients. Erlotinib co administered with RT and temozolomide was not efficacious and had an unacceptable toxicity.
Patients with 1–3 brain metastases (BM) often receive sterotactic radiosurgery (SRS) without whole brain radiotherapy (WBRT). SRS without WBRT carries a high rate of relapse in the central nervous ...system (CNS). This trial used sunitinib as an alternative to WBRT for post-SRS adjuvant therapy. Eligible patients with 1–3 newly diagnosed BM, RTOG RPA class 1–2, received sunitinib after SRS. Patients with controlled systemic disease were allowed to continue chemotherapy for their primary disease according to a list of published regimens (therapy + sunitinib) included in the protocol. Patients received sunitinib 37.5 or 50 mg/days 1–28 every 42 days until CNS progression. Neuropsychological testing and MRIs were obtained every two cycles. The primary endpoint was the rate of CNS progression at 6 months (PFS
6
) after SRS. Fourteen patients with a median age of 59 years were enrolled. Primary cancers included lung 43 %, breast 21 %, melanoma 14 %. Toxicity included grade 3 or higher fatigue in five patients and neutropenia in two patients. The CNS PFS
6
and PFS
12
were 43 ± 14 and 34 ± 14 %, respectively. Of the ten patients who completed >1 neurocognitive assessment, none showed cognitive decline. Sunitinib after SRS for 1–3 BM was well tolerated with a PFS
6
of 43 %. The prevention of progressive brain metastasis after SRS requires the incorporation of chemotherapy regimens to control the patient’s primary disease. Future trials should continue to explore the paradigm of secondary chemoprevention of BM after definitive local therapy.
Laser interstitial thermal therapy has been used as an ablative treatment for glioma; however, its development was limited due to technical issues. The NeuroBlate System incorporates several ...technological advances to overcome these drawbacks. The authors report a Phase I, thermal dose-escalation trial assessing the safety and efficacy of NeuroBlate in recurrent glioblastoma multiforme (rGBM).
Adults with suspected supratentorial rGBM of 15- to 40-mm dimension and a Karnofsky Performance Status score of ≥ 60 were eligible. After confirmatory biopsy, treatment was delivered using a rigid, gas-cooled, side-firing laser probe. Treatment was monitored using real-time MRI thermometry, and proprietary software providing predictive thermal damage feedback was used by the surgeon, along with control of probe rotation and depth, to tailor tissue coagulation. An external data safety monitoring board determined if toxicity at lower levels justified dose escalation.
Ten patients were treated at the Case Comprehensive Cancer Center (Cleveland Clinic and University Hospitals-Case Medical Center). Their average age was 55 years (range 34-69 years) and the median preoperative Karnofsky Performance Status score was 80 (range 70-90). The mean tumor volume was 6.8 ± 5 cm(3) (range 2.6-19 cm(3)), the percentage of tumor treated was 78% ± 12% (range 57%-90%), and the conformality index was 1.21 ± 0.33 (range 1.00-2.04). Treatment-related necrosis was evident on MRI studies at 24 and 48 hours. The median survival was 316 days (range 62-767 days). Three patients improved neurologically, 6 remained stable, and 1 worsened. Steroid-responsive treatment-related edema occurred in all patients but one. Three had Grade 3 adverse events at the highest dose.
NeuroBlate represents new technology for delivering laser interstitial thermal therapy, allowing controlled thermal ablation of deep hemispheric rGBM. CLINICAL TRIAL REGISTRATION NO.: NCT00747253 ( ClinicalTrials.gov ).
Abstract
BACKGROUND
Studies of bevacizumab monotherapy and TTFields monotherapy have shown activity but limited clinical benefit in patients with recurrent GBM. In an open label, single-arm, phase 2 ...clinical trial, the safety and efficacy of the combination of bevacizumab and TTFields was studied in patients with recurrent GBM.
METHOD
Bevacizumab-naïve patients with histologically confirmed GBM or other grade IV glioma, with recurrent disease after radiotherapy and temozolomide chemotherapy, were eligible. Bevacizumab dose was 10mg/kg intravenously every 2 weeks and TTFields was worn at least 18 hours daily. The primary endpoint was safety, progression-free survival at 6 months (PFS6) and overall survival at 12 months (OS12). Treatment was continued until disease progression or unacceptable toxicity. Survival outcomes were assessed using the Kaplan-Meier method. Treatment-related adverse events were reported according to CTCAE, v4.0 criteria.
RESULTS
25 patients were enrolled and 23 were eligible for data analysis: 18 (78%) men and 5 (22%) women, median age 60 years (range 17–78). 21 patients were Caucasian, 1 was African American and 1 of unknown race. Median follow-up was 6.0 months (range 2.4–22). Seven patients (30 %) had disease progression. Median PFS was 9.9 (95% CI: 6.7-NA) months. PFS rate at 6 months (PFS6) was 71% (95% CI: 0.54–0.94). Median overall survival was 9.9 (95%CI 7.3-NA) months. OS rate at 12 months (OS12) was 42% (95%CI 0.24–0.74). 7 patients (30%) had grade 3 toxicity (cough, dysphagia, muscle weakness, hyperglycemia, hypertension, psychosis, seizure, lymphopenia, transaminitis). 1 patient developed grade 4 muscle weakness in the lower extremities.
CONCLUSION
Treatment with the combination of bevacizumab and TTFields in patients with recurrent GBM is safe and feasible and has shown clinical efficacy.
Abstract
BACKGROUND
Glioblastoma (GBM) creates an immunosuppressive environment that allows tumor growth. Myeloid derived suppressor cells (MDSCs) mediate immunosuppression in GBMs. MDSCs are ...up-regulated in the blood of GBM patients. We have developed a novel strategy to target GBM immunosuppression using low dose 5-fluorouracil (5-FU) to target MDSCs. Marked MDSC depletion occurs at 5-FU doses in mice equivalent to <10% of the normal human dosing. Goal: proof of concept that MDSC suppression is feasible in GBM patients with low-dose capecitabine cap, (oral 5-FU analogue).
METHODS
Eligibility: Recurrent GBM in need of surgical resection; no prior cap or bevacizumab. Cohorts of 3–6 patients receive low-dose cap 150 mg/m2/d (dose level 1) for 7 days pre-surgery. Post-op, patients resume cap for one cycle after which bev is added. Concentrations of blood MDSCs, immune cells, and relevant secreted factors are measured at baseline; pre- and post-op; and after the addition of bev. Tumors are assayed for MDSCs and glioma stem-like cells (GSCs). Primary endpoint: MDSC and T-regulatory cell (T-reg) reduction after cap.
RESULTS
Seven patients have enrolled to date. In all patients MDSCs rose initially after resection (max rise 18% over baseline) and subsequently began to fall after cycle 2 (max reduction 6%). T-regs fell slightly (0–12%) in 5 of 7 patients. Cytotoxic T-cell (CTL) concentrations rose significantly (max 93%). CD3+ T-cells fell in 5 of 7 patients (max reduction 52%). Four of 7 (71%) of patients reached PFS6. Median PFS-6 months (2–14 mos). Median overall survival 10 months (5–16). Treatment-related SAEs: grade 3 dyspnea; grade 2 hemorrhage, non-neutropenic fever; and grade 1 hand-foot.
CONCLUSIONS
Low-dose capecitabine is associated with a modest reduction in MDSCs and T-regs and a significant increase in CTLs. Toxicity has been manageable. Four of 7 evaluable patients have reached 6 months free of progression. Dose escalation continues.
Abstract
BACKGROUND
The effectiveness of stereotactic radiosurgery (SRS) for recurrent glioblastoma (rGBM) remains uncertain. SRS has been associated with a high risk of radionecrosis in gliomas.
...OBJECTIVE
To determine the safety of dose escalation of single-fraction radiosurgery for rGBM in the setting of bevacizumab therapy.
METHODS
We conducted a prospective trial to determine the safety and synergistic benefit of higher doses of SRS administered with bevacizumab for rGBM. A single dose of bevacizumab was given prior to SRS and continued until progression. Dose-limiting toxicity was evaluated in successive cohorts of 3 patients.
RESULTS
Seven males and 2 females entered the study. The maximum linear diameter of the enhancing tumor was 2.58 cm (2.04-3.09). Prescription dose was escalated from 18 to 22 Gy. The radiosurgery target was chosen before the first dose of bevacizumab, about 1 wk prior to SRS treatment. Pre-SRS bevacizumab treatment was associated with a reduction of the mean volume of the enhancing lesion from 4.7 to 2.86 cm3 on the day of SRS (P = .103). No patient developed an acute side effect related to SRS treatment. The combination of SRS and bevacizumab resulted in a partial response in 3 patients and stable disease in 6 patients. Median progression-free and overall survival were 7.5 and 13 mo, respectively.
CONCLUSION
A single dose of bevacizumab prior to SRS permitted safe prescription dose escalation up to 22 Gy for rGBM. Further evaluation of the efficacy of SRS for rGBM should be performed in the setting of bevacizumab treatment.
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