Jeffrey J. Raizer

11549 Background: The validated CellSearch system (Janssen Diagnostics, LLC), utilizing an immunomagnetic CTC selection method based on EPCAM antibody conjugated ferroparticles, is an FDA-approved methodology for enumerating CTC from blood in pts with breast, prostate and colon cancers. The CellSearch system has been used to evaluate CSF CTC of pts with leptomeningeal metastasis (LM) and has demonstrated potential as a diagnostic marker and response to cancer treatment. We explored the use of CSF CTC enumeration in the follow-up of pts with LM from HER2+ cancers receiving intrathecal (IT) therapy, aimed at characterizing changes over time as a potential biomarker of treatment response. Methods: CSF from pts participating in an IRB-approved phase I/II dose escalation trial of IT trastuzumab for LM in HER2+ cancer (NCT01325207) was evaluated by CellSearch system. 3 ml CSF from a ventricular reservoir was collected for CSF CTC enumeration at pre-treatment Day 1 of each cycle and correlated with CSF cytology from the same sample, and with clinical and radiographic response. LM progression was defined as clinical, CSF cytologic or radiographic worsening. Results: 15 pts with HER2+ LM (14 breast, 1 colon) were enrolled; 13 were women. At baseline 7 pts had positive CSF cytology, the other patients had a diagnosis by MRI. Of the 15 pts, 10 had greater than 1 cycle of treatment to be evaluable; 5 pts progressed during cycle 1 (Table). Mean CSF CTC at baseline was 82 per 3ml (range 0-200); 2 pts had no detectable CSF CTCs. A numerical decrease in CSF CTC was observed in 5 pts after cycle 1 and remained low (mean =9.5, range 0-92) while disease was stable. 3 pts (pts.3, 4 and 7) demonstrated a rise in CSF CTCs roughly 1 month prior to disease progression. Conclusions: Changes in CSF CTCs enumeration in response to treatment may allow quantitative surveillance of treatment response. CSF CTCs may serve as a platform to assess treatment response or as an early biomarker of LM progression and should be further investigated. Clinical trial information: NCT01325207. [Table: see text]

One resistance mechanism in malignant gliomas (MG) involves nuclear factor-κB (NF-κB) activation. Bortezomib prevents proteasomal degradation of NF-κB inhibitor α (NFKBIA), an endogenous regulator of NF-κB signaling, thereby limiting the effects of NF-κB on tumor survival and resistance. A presurgical phase II trial of bortezomib in recurrent MG was performed to determine drug concentration in tumor tissue and effects on NFKBIA. Patients were enrolled after signing an IRB approved informed consent. Treatment was bortezomib 1.7 mg/m² IV on days 1, 4 and 8 and then surgery on day 8 or 9. Post-operatively, treatment was Temozolomide (TMZ) 75 mg/m² PO on days 1–7 and 14–21 and bortezomib 1.7 mg/m² on days 7 and 21 [1 cycle was (1) month]. Ten patients were enrolled (8 M and 2 F) with 9 having surgery. Median age and KPS were 50 (42–64) and 90 % (70–100). The median cycles post-operatively was 2 (0–4). The trial was stopped as no patient had a PFS-6. All patients are deceased. Paired plasma and tumor bortezomib concentration measurements revealed higher drug concentrations in tumor than in plasma; NFKBIA protein levels were similar in drug-treated vs. drug-naïve tumor specimens. Nuclear 20S proteasome was less in postoperative samples. Postoperative treatment with TMZ and bortezomib did not show clinical activity. Bortezomib appears to sequester in tumor but pharmacological effects on NFKBIA were not seen, possibly obscured due to downregulation of NFKBIA during tumor progression. Changes in nuclear 20S could be marker of bortezomib effect on tumor.

2051 Background: There is no standard therapy for recurrent anaplastic glioma (AG). Salvage therapies include alkylator-based chemotherapy (temozolomide [TMZ] or lomustine [CCNU]), re-resection with or without carmustine implants, re-irradiation and bevacizumab. Bendamustine is a novel bifunctional alkylator with CNS penetration but never evaluated in AG. Objective: Assess response and toxicity of bendamustine in bevacizumab naïve recurrent AG following prior radiotherapy (RT) and TMZ in a prospective Phase II trial. Methods: 26 adults (16 males; 10 females: median age 40 years {range 30-65}) with RT and TMZ refractory recurrent AG (14 anaplastic astrocytoma, 7 anaplastic oligodendroglioma, 5 anaplastic oligoastrocytoma) were treated with bendamustine. 12 patients were treated at 1^st and 14 at 2^nd recurrence. Prior salvage therapy included re-resection in 14 (12 with 2^nd and 2 with 3^rd resection), chemotherapy in 11 and re-RT in 2. A cycle of bendamustine was defined as 2 consecutive days of treatment (100mg/m²/day) administered once every 4 weeks (maximum number of cycles 6). Success of treatment was defined as progression free survival (PFS) at 6 months > 40%. Results: Grade 3 treatment-related toxicities included lymphopenia (11 patients), myalgia, pneumonia, diarrhea, leukopenia, allergic reaction and thrombocytopenia in 1 patient each. Three patients had grade 4 lymphopenia. No grade 5 toxicities were seen. One patient discontinued therapy due to toxicity (allergic reaction). Bendamustine dose was delayed in 3 patients (total of 5 events). There were no dose reductions. The median number of cycles of therapy was 3 (range 1-8). Best radiographic response was progressive disease in 12 (46%), stable disease in 13 (50%) and partial response in 1 (4%). Response did not differ by histology. Median PFS was 2.7 months (range 1-52 months), 6-month PFS was 27% and 12-month PFS was 8%. Conclusions: In this small prospective series of patients with recurrent AG refractory to TMZ and bevacizumab naive, bendamustine appears to have modest single agent activity though not meeting pre-specified criteria (40% 6-month PFS) and manageable toxicity. The study was supported in part through research funds provided by TEVA Pharmaceuticals and the National Comprehensive Cancer Network. Clinical trial information: NCT00823797.

We describe the clinical and therapeutic course of a 51-year-old woman with HER-2+ breast cancer who developed leptomeningeal (LM) and spinal cord metastases after 8 years of stable disease on combination therapy with intravenous (IV) trastuzumab. Due to progressive CNS disease, intrathecal (IT) trastuzumab was introduced to enhance HER-2+ therapy into the CSF space. A combination HER-2+ targeted approach achieved clinical remission with stable disease in our patient 46 months after she was diagnosed with LM metastases. However, spinal cord C-1 metastasis was not fully controlled with IT trastuzumab, ultimately leading to the patient’s respiratory compromise. In our patient, IT trastuzumab immunotherapy improved prognosis and was an effective strategy to manage HER-2+ LM disease. Given alone or alongside other anti-HER-2+ therapeutics with sufficient CNS penetration, IT trastuzumab could extend the lifespan of patients with leptomeningeal and CNS metastases.

Low-grade gliomas are slower growing than their high-grade counterparts. They account for 10–20 % of all primary brain tumors. Median survival is between 4.7 and 9.8 years. The goal of treatment is to prolong overall survival while maintaining good quality of life (QOL). Recent data favors early surgical resection. EOR is associated with delayed tumor recurrence and improved survival. Additional therapy with chemotherapy or radiation is indicated in patients with high-risk features. Lower doses (between 45 and 50.4 Gy) have been shown to be as effective without adverse effects compared to higher doses. Recent trials have shown benefit in combining chemotherapy with radiation compared to radiation alone. The optimal chemotherapeutic regimen (PCV or temozolomide (TMZ)) remains unknown, although TMZ is easier to administer and better tolerated by patients. Novel molecular markers including 1p/19q chromosomal codeletion and isocitrate dehydrogenase 1 (IDH1) mutation have been correlated with treatment response and survival.

BackgroundGiven the neurocognitive impairment experienced by many patients with malignant gliomas, caregiver reports can be critical in assessing the quality of life (QOL) of these patients. In this study, we explored whether assessment of patient QOL by the primary caregiver shows concordance with the patient's self-reported QOL, and we quantified the burden faced by caregivers.MethodsQOL of 45 patients was evaluated by both the patient and primary caregiver on 3 or more separate occasions using the Functional Assessment of Cancer Therapy-Brain (FACT-Br) instrument, and concordance between the 2 reports was evaluated. Caregiver burden was measured using the Caregiver Quality of Life Index-Cancer (CQOL-C) instrument.ResultsOverall, good concordance was observed between the patient and caregiver FACT-Br reports (intraclass correlation coefficient = 0.74). Patient-reported FACT-Br scores were 4.75 (95% CI, 1.44–8.05) points higher than paired caregiver reports on the 200-point scale (P = .008); however, this difference did not achieve clinical significance. Caregiver burden, as measured by the CQOL-C, was significantly greater among caregivers in this study than those previously reported for caregivers of patients with lung, breast, or prostate cancer (P < .001).ConclusionsDespite minor discrepancies in caregiver assessments of patient QOL relative to patient self-reports, our results suggest that the caregiver assessments can serve as adequate proxies for patient reports. Our results also illustrate the particularly heavy burden faced by caregivers of patients with malignant glioma. Further research into both of these areas is warranted.

When surgery and radiation are no longer treatment options, salvage systemic therapy has been used for recurrent meningiomas with little compelling evidence to suggest effectiveness. Patients with surgery and radiation refractory recurrent meningiomas were treated with the oral multifunctional tyrosine kinase inhibitor PTK787/ZK 222584 (PTK787) at a dose of 500 mg twice a day. Each treatment cycle was 4 weeks with MRI done every 8 weeks. Twenty-five patients (14 men; 11 women) with a median age of 59 years and KPS of 80 were treated. Meningioma WHO Grade was I in 2 patients, II in 14 patients and III in 8 patients; 1 patient had a hemangiopericytoma. All patients had prior surgery, external beam radiation therapy or radiosurgery and 11 patients prior systemic chemotherapy. Median number of cycles of PTK 787 administered was 4 (range <1–22). Best response in the 22 evaluable patients was stable disease in 15 (68.2 %). Predominant PTK787 related toxicities included fatigue (60 %), hypertension (24 %) and elevated transaminases (24 %). Grade II patients had a progression free survival (PFS)-6 of 64.3 %, a median PFS of 6.5 months and an overall survival (OS) of 26.0 months; grade III patients had a PFS-6 of 37.5 %, median PFS of 3.6 months and OS 23 months. PTK787 was modestly toxic at the dose of 500 mg administered twice per day. Activity as determined by PFS-6 suggests that targeting PDGF/VEGF pathway warrants further investigation.