Johnny Duerinck

Correlation of EGFR, IDH1 and PTEN status with the outcome of patients with recurrent glioblastoma treated in a phase II clinical trial with the EGFR-blocking monoclonal antibody cetuximab

Mutation and gene amplification of the epithelial growth factor receptor (EGFR) is one of the most common genetic alterations in glioblastoma (GB). EGFR is, therefore, an attractive molecular target for the treatment of GB. EGFR-targeted therapies however have been largely ineffective in clinical trials. In this study, we investigated the correlation between the EGFR gene amplification status, expression of the EGFR variant III (EGFRvIII) and EGFR variant IV (EGFRvIV) mutations, expression of the phosphatase and tensin homologue gene on chromosome 10 (PTEN) and mutation of the isocitrate dehydrogenase 1 (IDH1) gene and the survival of patients suffering from recurrent glioblastoma who were treated with the EGFR-targeted monoclonal antibody cetuximab in a prospective phase II clinical trial. EGFR amplification was detected in 19 out of 35 GB (54%), EGFRvIII expression in 11 (31.4%) and EGFRvIV expression in 7 (20%). The EGFRvIII and EGFRvIV mutations were exclusively found in GB with EGFR amplification and were almost mutually exclusive with IDH1 mutation (EGFRvIII mutation was found in 1 out of 11 GB with an IDH1 mutation). Patients with an EGFR amplification lacking EGFRvIII expression had a significantly superior progression free survival (PFS) and a numerical better overall survival (OS) following treatment with cetuximab [median PFS 3.03 vs. 1.63 months (p=0.006); median OS 5.57 vs. 3.97 months (p=0.12)]. Within the subgroup of patients with EGFR amplification, patients with EGFRvIII positive glioblastoma had a worse survival [median PFS 1.63 vs. 3.03 months (p=0.01); median OS 3.27 vs. 5.57 months (p=0.08)]. Our observations indicate that the type of EGFR mutation may determine the outcome of GB patients treated with cetuximab. Prospective investigation of both the EGFR amplification and mutation status in clinical trials with EGFR-targeted therapies for GB is indicated.

Radiation necrosis of the brain in melanoma patients successfully treated with ipilimumab, three case studies.

Metastasis to the brain is a frequent event in patients with advanced melanoma. Despite treatment with neurosurgery, pancranial irradiation and high-precision conformal radiotherapy, the prognosis of patients suffering from melanoma brain metastasis has remained very poor. Ipilimumab is a new effective immunotherapy for the treatment of advanced melanoma and has demonstrated activity against brain metastases. We report three patients successfully treated with ipilimumab who subsequently developed focal necrosis of the brain following prior radiotherapy of their melanoma brain metastases. As new active systemic treatment options become available that improve the survival of patients with melanoma brain metastases, adequate diagnosis and management of the late sequela from radiation to the brain is likely to gain importance in the management of these patients.

Symptomatic Histologically Proven Necrosis of Brain following Stereotactic Radiation and Ipilimumab in Six Lesions in Four Melanoma Patients

Four cases previously treated with ipilimumab with a total of six histologically confirmed symptomatic lesions of RNB without any sign of active tumour following stereotactic irradiation of MBM are reported. These lesions were all originally thought to be disease recurrence. In two cases, ipilimumab was given prior to SRT; in the other two ipilimumab was given after SRT. The average time from first ipilimumab to RNB was 15 months. The average time from SRT to RNB was 11 months. The average time from first diagnosis of MBM to last follow-up was 20 months at which time three patients were still alive, one with no evidence of disease. These cases represent approximately three percent of the total cases of melanoma and ten percent of those cases treated with ipilimumab irradiated in our respective centres collectively. We report this to highlight this new problem so that others may have a high index of suspicion, allowing, if clinically warranted, aggressive surgical salvage, possibly resulting in increased survival. Further studies prospectively collecting data to understand the denominator of this problem are needed to determine whether this problem is just the result of longer survival or whether there is some synergy between these two modalities that are increasingly being used together.

Retrograde C0-C1 Insertion of Cervical Plate Electrode for Chronic Intractable Neck and Arm Pain

OBJECTIVE Spinal cord stimulation is an effective treatment for chronic neuropathic pain after spinal surgery. In addition to the most common placement of electrodes at the thoracic level for low back and leg pain, electrodes can also be placed on a cervical level in patients with chronic neck and upper limb pain. Surgical insertion of plate electrodes via an orthodromal direction requires a partial laminectomy. Therefore, the authors describe a surgical technique using retrograde insertion of a plate electrode to avoid laminectomy. METHODS Six patients with uncontrolled neck and upper limb pain despite optimal analgesic medication were treated with a surgical electrode placed at the C1-C2 level via a retrograde placement technique without laminectomy. RESULTS All patients received stimulation paresthesias at the desired regions and reported significant pain reduction in the neck and arm regions. CONCLUSION This retrograde placement of plate electrodes enables cervical lordosis to be overcome and results in adequate stimulation of the upper cervical region, which is mandatory to reduce neck and shoulder pain without laminectomy.

An observational study of the first experience with Bevacizumab for the treatment of patients with recurrent high-grade glioma in two belgian university hospitals

Background. Bevacizumab (BEV), a humanized immunoglobulin G1 monoclonal antibody that inhibits VEGF has demonstrated activity against recurrent high-grade gliomas (HGG) in phase II clinical trials. Patients and Methods. Data were collected from patients with recurrent HGG who initiated treatment with BEV outside a clinical trial protocol at two Belgian university hospitals. Results. 19 patients (11 M/8 F) were administered a total of 138 cycles of BEV (median 4, range 1–31). Tumor response assessment by MRI was available for 15 patients; 2 complete responses and 3 partial responses for an objective response rate of 26% for the intent to treat population were observed on gadolinium-enhanced T1-weighted images; significant regressions on T2/FLAIR were documented in 10 out of 15 patients (67%). A reduced uptake on PET was documented in 3 out of 4 evaluable patients. The six-month progression-free survival was 21% (95% CI 2.7–39.5). Two patients had an ongoing tumor response and remained free from progression after 12 months of BEV treatment. Conclusions. The activity and tolerability of BEV were comparable to results from previous prospective phase II trials. Reduced uptake on PET suggests a metabolic response in addition to an antiangiogenic effect in some cases with favorable clinical outcome.

Randomized phase II trial comparing axitinib with the combination of axitinib and lomustine in patients with recurrent glioblastoma

Axitinib is a small molecule tyrosine kinase inhibitor with high affinity and specificity for the family of vascular endothelial growth factor receptors. It has previously demonstrated anti-tumor activity in a small cohort of patients with recurrent glioblastoma (rGB). We conducted a non-comparative randomized phase II clinical trial investigating axitinib monotherapy versus axitinib plus lomustine (LOM) in patients with rGB. Primary endpoint was 6 month progression-free survival (6mPFS). Patients who progressed on axitinib-monotherapy were allowed to cross-over. Between August 2011 and July 2015, 79 patients were randomized and initiated axitinib monotherapy (n = 50; AXI) or axitinib plus lomustine (n = 29; AXILOM). Median age was 55y [range 18–80], 50M/28F. Baseline characteristics were well balanced between study arms. Nineteen patients in the AXI-arm crossed-over at the time of progression. Treatment was generally well tolerated. AXILOM patients were at higher risk for grade 3/4 neutropenia (0 vs. 21%) and thrombocytopenia (4 vs. 29%). Best Overall Response Rate (BORR) in the AXI-arm was 28 vs. 38% in the AXILOM-arm. 6mPFS was 26% (95% CI 14–38) versus 17% (95% CI 2–32) for patients treated in the AXI versus AXILOM-arms, respectively. Median overall survival was 29 weeks (95% CI 20–38) in the AXI-arm and 27.4 weeks (95% CI 18.4–36.5) in the AXILOM-arm. MGMT-promoter hypermethylation and steroid treatment at baseline correlated significantly with PFS and OS. We conclude from these results that axitinib improves response rate and progression-free survival in patients with rGB compared to historical controls. There is no indication that upfront combination of axitinib with LOM improves results (European Clinical Trials Database (EudraCT) Study Number: 2011-000900-16).

Disc Fragment Herniectomy Through a Facet Joint Quadrantectomy for Extraforaminal Lumbar Herniation: Technique and Results

BACKGROUND Extraforaminal lumbar disc herniation (EFLDH) accounts for 7%-12% of all lumbar disc herniations. We report on a surgical technique for EFLDH, which requires only minimal resection of the facet joint and also allows access to the preforaminal space, if necessary. METHODS The medical records of 61 consecutive patients treated with disc fragment herniectomy through a facet joint quadrantectomy for EFLDH at the Universitair Ziekenhuis Brussel were critically evaluated with respect to preoperative clinical signs and symptoms, surgery-related complications and outcome at 6 weeks after intervention. Patient satisfaction after the surgery was evaluated using the MacNab classification. RESULTS The prevalence of leg pain decreased from 100% before the intervention to 19.7% at follow-up. Only 9 patients (14.8%) suffered from residual motor deficit at follow-up, compared with 37 patients (60.7%) in the preoperative situation. The postoperative improvement was highly significant for all parameters (P < 0.0001) and this evolution is also reflected in the MacNab classification showing 62.3% excellent, 23.0% good, 13.1% fair, and only 1.6% poor satisfaction. Using logistic regression analysis, only the presence of a preoperative sensory deficit was found to be an independent predictor for excellent patient satisfaction on the MacNab classification. CONCLUSIONS Disc fragment herniectomy through a facet joint quadrantectomy for EFLDH is a safe and minimal invasive technique resulting in very satisfactory results. Preservation of facet joint stability and the possibility to convert to a classic approach to reach for preforaminal components, if necessary, are major advantages of this technique.

Focal radiation necrosis of the brain in patients with melanoma brain metastases treated with pembrolizumab

Up to 60% of patients with metastatic melanoma develop melanoma brain metastasis (MBM) during the course of their disease. Surgery, radiosurgery (SRS), stereotactic radiotherapy (SRT), and whole‐brain radiation therapy (WBRT) or combinations of these are commonly used local treatment modalities. Inhibitory monoclonal antibodies against the CTLA‐4 and PD‐1 immune checkpoint receptors significantly improved the survival of metastatic melanoma patients, including patients with MBM. This prolonged survival, and potentially also the immunostimulatory mechanisms, may expose patients to a higher risk for long‐term complications such as focal postradiation necrosis of the brain (RNB).

P16.09VALUE OF FET-PET EVALUATION IN PATIENTS TREATED WITH AXITINIB

INTRODUCTION: VEGF/VEGFR targeted therapy for recurrent glioblastoma (rGB) normalizes tumour vasculature and restores the blood-brain barrier (BBB), resulting in decreased contrast enhancement and reduced peritumoral oedema. MRI-T2/FLAIR images are useful to document non-contrast-enhancing tumor progression, but its specificity is limited. Since the uptake of Fluoroethyltyrosine in GB reflects tumor metabolism and not BBB-integrity, the extent of (18)F-fluoroethyltyrosine (FET) uptake, as assessed by positron emission tomography (PET), may be of value in assessing the tumor response to treatment with small molecule VEGFR-inhibitors such as axitinib., MATERIAL AND METHODS: We evaluated patients with rGB treated with axitinib with MRI and FET-PET (static images acquired 45 min. after tracer administration) at baseline. In patients demonstrating a response on MRI (using RANO criteria), FET-PET was repeated. For 18F-FET PET, reduction of the metabolically active volume (Sum of tumour associated pixels with target-to-normal brain ratio of ≥1.5) was considered as a metabolic response to treatment. RESULTS: 15 patients treated with axitinib were evaluated with MRI and FET-PET. On MRI, 2 pts had CR and 4 PR. All responses on MRI were also characterized by a decrease in FET-active tumor volume. The extent of reduction of metabolically active volume did not correlated with the extent of tumor regression on Gd- MRI: the 2 patients with CR on MRI had a 65% and 43% decrease on FET-PET, respectively, whereas the decrease on FET-PET ranged between 26 and 100% in the patients with PR on MRI. A trend was observed between a higher baseline FET-active tumor volume and an increased progression-free survival (PFS) and overall survival (OS). A greater reduction of the metabolically active volume did correlate with longer PFS and OS (logrank p > 0,001 and p < 0,025, respectively). CONCLUSION: In patients with rGB treated with the VEGFR-inhibitor axitinib, baseline FET-PET has prognostic value. Response evaluation based on FET-PET is complementary to MRI based assessment and may prove superior in predicting survival on treatment with axitinib. Our preliminary findings deserve further evaluation in a larger series.

O10.07RANDOMIZED PHASE II STUDY OF AXITINIB VS. STANDARD OF CARE IN PATIENTS WITH RECURRENT GLIOBLASTOMA

INTRODUCTION: Glioblastoma (GB) associated neo-angiogenesis is mediated by vascular endothelial growth factor receptor (VEGFR) signal transduction. Axitinib is an oral small molecule tyrosine kinase inhibitor with high affinity and specificity for the VEGF-receptors, approved for the treatment of metastatic renal cell carcinoma. METHODS: Axitinib (5 mg BID starting dose) vs. best alternative choice of therapy was studied in an open label, randomized, phase II clinical trial in patients (pts) with recurrent GB. Six-month progression-free survival (6mPFS) was the primary endpoint using Flemings single-stage procedure. RESULTS: Between Sep 2011 and Oct 2013, 44 pts who failed surgery, RT and temozolomide were randomized 1:1 at 3 sites. Median age 54y (range 20-79), 33M/11F, WHO-PS 0/1/2/3: 6, 26, 11, and 1 pt. In the control arm 20 pts received bevacizumab and 2 pts received lomustine at standard doses. Axitinib (n = 22) was generally well tolerated. Most common axitinib related AEs consisted of dysphonia (3x G2), fatigue (6x G2, 2x G3), hypertension (5x G2), oral hyperesthesia (7x G2, 1x G3), diarrhea (2x G2, 2x G3), and hypothyroidism (3x G2). In 4 pts axitinib dosing was interrupted and subsequently dose reduced because of toxicity; in 4 other pts axitinib was dose escalated to 7 or 10 mg BID (2 pts each). The confirmed best overall tumor response rate by RANO criteria was 28% in the axitinib arm (2 CR / 4 PR) vs. 23% in the control arm (1 CR / 4 PR). Five additional pts in the axitinib-arm and 1 additional patient in the control-arm had an unconfirmed respons, and respectively 5 and 7 patients had a SD; 1pt in each arm was not evaluable for tumor response. Corticosteroids could be stopped in 4/12 and tapered in an additional 5/12 pts in the axitinib arm. At baseline all pts had an increased uptake on 18F-FET PET and a magnetic resonance spectroscopy (MRS) signal pattern showing an increased level of choline (Cho) and a decreased level of N-acetylaspartate (NAA) at the site of rGB. A decrease (-26 to -100%) of SUVmax/background on 18F-FET PET was documented in 6/7 pts on axitinib at the time of response on MRI. MRS-spectra obtained at the time of response and progression are currently being analysed. After a median follow-up of 10.5 mths, the 6mPFS for axitinib was 22% (95% CI 5-40) vs. 19% (95% CI 2-36) for the control arm. Median PFS and OS were respectively 2.9 vs. 2.6 mths, and 10.3 vs. 7.4 mths for pts treated in the axitinib vs. control arm. CONCLUSIONS: Axitinib has single-agent activity and manageable toxicity in pts with recurrent GB. The survival on the axitinib arm was comparable to that on the contemporary control arm. Tumor response on MRI is accompanied by decreased uptake of tracer on 18F-FET PET scan. Response characteristics in MRS are currently under evaluation. Further evaluation of axitinib for recurrent GB is warranted.