Proton therapy for adult medulloblastoma: Acute toxicity and disease control outcomes.

PURPOSE: We report disease control, survival outcomes, and treatment-related toxicity among adult medulloblastoma patients who received proton craniospinal irradiation (CSI) as part of multimodality therapy. METHODS: We reviewed 20 adults with medulloblastoma (≥ 22 years old) who received postoperative proton CSI ± chemotherapy between 2008 and 2020. Patient, disease, and treatment details and prospectively obtained patient-reported acute CSI toxicities were collected. Acute hematologic data were analyzed. RESULTS: Median age at diagnosis was 27 years; 45% of patients had high-risk disease; 75% received chemotherapy, most (65%) after CSI. Eight (40%) patients received concurrent vincristine with radiotherapy. Median CSI dose was 36GyE with a median tumor bed boost of 54GyE. Median duration of radiotherapy was 44 days. No acute ≥ grade 3 gastrointestinal or hematologic toxicities attributable to CSI occurred. Grade 2 nausea and vomiting affected 25% and 5% of patients, respectively, while 36% developed acute grade 2 hematologic toxicity (36% grade 2 leukopenia and 7% grade 2 neutropenia). Those receiving concurrent chemotherapy with CSI had a 38% rate of grade 2 hematologic toxicity compared to 33% among those not receiving concurrent chemotherapy. Among patients receiving adjuvant chemotherapy (n = 13), 100% completed ≥ 4 cycles and 85% completed all planned cycles. With a median follow-up of 3.1 years, 4-year actuarial local control, disease-free survival, and overall survival rates were 90%, 90%, and 95%, respectively. CONCLUSIONS: Proton CSI in adult medulloblastoma patients is very well tolerated and shows promising disease control and survival outcomes. These data support the standard use of proton CSI for adult medulloblastoma.

Primary Tumoral Calcinosis in a Pediatric Patient: A Rare Presentation.

Tumoral calcinosis is a benign, progressive disorder characterized by massive periarticular deposition of calcium salts into subcutaneous and deeper tissue layers. While a majority of cases present secondary to underlying metabolic disorders, it can rarely present as a primary, idiopathic phenomenon. We present an atypical case of a pediatric patient with a large, ulcerated pedal soft tissue mass found to be consistent with primary tumoral calcinosis. This was confirmed by histopathologic analysis and comprehensive metabolic workup. The patient underwent surgical excision of the mass, with complete resolution of symptoms and no recurrence after a 1-year follow-up period.

A randomized phase I/II study of ABT-888 in combination with temozolomide in recurrent temozolomide resistant glioblastoma: an NRG oncology RTOG group study.

This study tested the hypothesis that ABT-888 (velparib), a poly (ADP-ribose) polymerase (PARP) inhibitor, can modulate temozolomide (TMZ) resistance in recurrent TMZ refractory glioblastoma patients. The combination regimen (TMZ/ABT-888) was tested using two randomized schedules (5 vs. 21 days), with 6-month progression free survival (PFS6) as the primary endpoint. The maximum tolerated dose (MTD) for TMZ using the 21 day of 28 TMZ schedule, in concert with 40 mg BID ABT-888 was determined in a phase I portion of this study, and previously reported to be 75 mg/m(2) (arm1). The MTD for ABT-888 (40 mg BID) and the 5 of 28 day TMZ (150-200 mg/m(2)) schedule was known from prior trials (arm2). Two cohorts were studied: bevacizumab (BEV) naïve (n = 151), and BEV refractory (n = 74). Overall ten patients were ineligible. The incidence rate of grade 3/4 myelosuppression over all was 20.0 %. For the BEV refractory cohort, the PFS 6 was 4.4 %; for the BEV naïve cohort, PFS6 was 17 %. Overall survival was similar for both arms in both the BEV naïve [median survival time (MST) 10.3 M; 95 % CI 8.4-12] and BEV refractory cohort (MST 4.7 M; 95 %CI 3.5-5.6). The median PFS was essentially the same for both arms and both cohorts at ~2.0 M (95 % CI 1.9-2.1).

Bevacizumab for glioblastoma refractory to vascular endothelial growth factor receptor inhibitors.

Glioblastoma (GBM) is a highly vascular tumor dependent on angiogenesis through the vascular endothelial growth factor (VEGF) signaling cascade. Inhibition of VEGF signaling is an important therapeutic strategy. We report our experience with bevacizumab (BEV), a VEGF targeting antibody, following failure of a VEGF receptor targeting tyrosine kinase inhibitor (TKI). We retrospectively identified patients treated on clinical trials with VEGFR-TKIs for recurrent GBM followed by BEV at next recurrence. Survival was estimated by the Kaplan-Meier method. Fourteen patients were identified (six women; median age 57). All received VEGFR-TKIs (sunitinib 11, cediranib 2, sorafenib 1) then BEV at next recurrence. There were no radiographic responses to VEGFR-TKIs; best response was stable disease in 50% (7/14). Patients received BEV alone (21%, 3/14) or in combination with chemotherapy (79%, 11/14). On BEV, 29% (4/14) had a partial response, and 36% (5/14) stabilized. Of evaluable patients, 42% (5/12) had neurological improvement and 56% (5/9) reduced corticosteroid requirement. Median survival on BEV was 7.8 months (95% CI 4.0-15.8), median progression-free survival (PFS) was 4.0 months (95% CI 1.6-10.5), and the 6-month PFS rate was 29% (95% CI 9-52). Our radiographic and survival outcomes with BEV following progression after VEGFR-TKIs are similar to data from studies of BEV as initial salvage therapy, although our sample size was small. Prior exposure to VEGFR-TKIs may not preclude response to BEV, but sensitivity to BEV may be lower following more robust VEGFR inhibition.

Recent innovations in the management of low-grade gliomas.

OPINION STATEMENT: Advancement in the understanding of biologic mechanisms of low-grade glioma pathophysiology has allowed the modern era of patient-specific genetic profiling, molecular biology, and neuroimaging to design new methods of surgery, radiation, and chemotherapy in hopes of preventing malignant transformation and improving outcomes. Recent innovations in the understanding of MGMT promoter methylation, IDH1 and IDH2 mutations, temozolomide chemotherapy, vascular monoclonal antibody treatment, use of radiation therapy, choice of antiepileptic drugs, surgical resection, and neuroimaging of low-grade gliomas are reviewed.

Operative Management: Plantar Plate.

The plantar plate is a vital structure for maintaining lesser metatarsophalangeal joint (MPJ) stability. Its primary role is to provide static stabilization of the MPJs, working in conjunction with the long and short flexor and extensor tendons. When insufficiency or attenuation of the plantar plate occurs, a sagittal plane deformity will slowly develop, eventually leading to a "crossover toe" transverse plane deformity. Coughlin coined this descriptive term to describe the later stages of deformity, most commonly affecting the second MPJ. Shortly after, Yu and Judge elaborated on this condition describing it as "predislocation syndrome," an inflammatory condition affecting the plantar plate causing pain and instability, which could progress to subluxation at the MPJ.

Biologics in the Treatment of Plantar Fasciitis.

Plantar fasciitis has been considered an acute inflammatory disorder. However, the local histologic findings represent a more chronic, degenerative state without inflammation. Patients may be stuck in a chronic state of cyclical inflammation leading to tissue degeneration, refractory symptoms, and disability. This idea process has influenced the treatment approach of some practitioners who have implemented the idea of regenerative medicine and use of biologic adjuvants in the treatment of plantar heel pain. Biologic therapies provide many different cellular components, growth factors, and proteins to restore normal tissue biology and are a useful adjunct in the treatment of recalcitrant plantar fasciitis.

A phase 1 trial of the histone deacetylase inhibitor AR-42 in patients with neurofibromatosis type 2-associated tumors and advanced solid malignancies.

PURPOSE: Given clinical activity of AR-42, an oral histone deacetylase inhibitor, in hematologic malignancies and preclinical activity in solid tumors, this phase 1 trial investigated the safety and tolerability of AR-42 in patients with advanced solid tumors, including neurofibromatosis type 2-associated meningiomas and schwannomas (NF2). The primary objective was to define the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs). Secondary objectives included determining pharmacokinetics and clinical activity. METHODS: This phase I trial was an open-label, single-center, dose-escalation study of single-agent AR-42 in primary central nervous system and advanced solid tumors. The study followed a 3 + 3 design with an expansion cohort at the MTD. RESULTS: Seventeen patients were enrolled with NF2 (n = 5), urothelial carcinoma (n = 3), breast cancer (n = 2), non-NF2-related meningioma (n = 2), carcinoma of unknown primary (n = 2), small cell lung cancer (n = 1), Sertoli cell carcinoma (n = 1), and uveal melanoma (n = 1). The recommended phase II dose is 60 mg three times weekly, for 3 weeks of a 28-day cycle. DLTs included grade 3 thrombocytopenia and grade 4 psychosis. The most common treatment-related adverse events were cytopenias, fatigue, and nausea. The best response was stable disease in 53% of patients (95% CI 26.6-78.7). Median progression-free survival (PFS) was 3.6 months (95% CI 1.2-9.1). Among evaluable patients with NF2 or meningioma (n = 5), median PFS was 9.1 months (95% CI 1.9-not reached). CONCLUSION: Single-agent AR-42 is safe and well tolerated. Further studies may consider AR-42 in a larger cohort of patients with NF2 or in combination with other agents in advanced solid tumors. TRIAL REGISTRATION: NCT01129193, registered 5/24/2010.

Phase I trial of intracerebral convection-enhanced delivery of carboplatin for treatment of recurrent high-grade gliomas.

BACKGROUND: Carboplatin is a potent cytoreductive agent for a variety of solid tumors. However, when delivered systemically, clinical efficacy for the treatment of high grade gliomas is poor due to limited penetration across the blood-brain barrier (BBB). Direct intracerebral (IC) convection-enhanced delivery (CED) of carboplatin has been used to bypass the BBB and successfully treat the F98 rat glioma. Based on these studies, we initiated a Phase I clinical trial. OBJECTIVE: This Phase I clinical trial was conducted to establish the maximum tolerated dose and define the toxicity profile of carboplatin delivered intracerebrally via convection enhanced delivery (CED) for patients with high grade glial neoplasms. METHODS: Cohorts of 3 patients with recurrent WHO grade III or IV gliomas were treated with escalating doses of CED carboplatin (1-4 µg in 54mL over 72 hours) delivered via catheters placed at the time of recurrent tumor resection. The primary outcome measure was determination of the maximum tolerated dose (MTD). Secondary outcome measures included overall survival (OS), progression-free survival (PFS), and radiographic correlation. RESULTS: A total of 10 patients have completed treatment with infusion doses of carboplatin of 1µg, 2µg, and 4µg. The total planned volume of infusion was 54mL for each patient. All patients had previously received surgery and chemoradiation. Histology at treatment include GBM (n = 9) and anaplastic oligodendroglioma (n = 1). Median KPS was 90 (range, 70 to 100) at time of treatment. Median PFS and OS were 2.1 and 9.6 months after completion of CED, respectively. A single adverse event possibly related to treatment was noted (generalized seizure). CONCLUSIONS: IC CED of carboplatin as a potential therapy for recurrent malignant glioma is feasible and safe at doses up to 4µg in 54mL over 72 hours. Further studies are needed to determine the maximum tolerated dose and potential efficacy.

Complete and Durable Responses in Primary Central Nervous System Posttransplant Lymphoproliferative Disorder with Zidovudine, Ganciclovir, Rituximab, and Dexamethasone.

Purpose: Primary central nervous system posttransplant lymphoproliferative disorder (PCNS-PTLD) is a complication of solid organ transplantation with a poor prognosis and typically associated with Epstein-Barr virus (EBV). We hypothesized EBV lytic-phase protein expression would allow successful treatment with antiviral therapy.Patients and Methods: Thirteen patients were treated with zidovudine (AZT), ganciclovir (GCV), dexamethasone, and rituximab in EBV+ PCNS-PTLD. Twice-daily, intravenous AZT 1,500 mg, GCV 5 mg/kg, and dexamethasone 10 mg were given for 14 days. Weekly rituximab 375 mg/m2 was delivered for the first 4 weeks. Twice-daily valganciclovir 450 mg and AZT 300 mg started day 15. Lytic and latent protein expression was assessed using in situ hybridization and immunohistochemistry. Immunoblot assay assessed lytic gene activation. Cells transfected with lytic kinase vectors were assessed for sensitivity to our therapy using MTS tetrazolium and flow cytometry.Results: The median time to response was 2 months. Median therapy duration was 26.5 months. Median follow-up was 52 months. The estimated 2-year overall survival (OS) was 76.9% (95% CI, 44.2%-91.9%). Overall response rate (ORR) was 92% (95% CI, 64%-100%). BXLF1/vTK and BGLF4 expression was found in the seven tumor biopsies evaluated. Lytic gene expression was induced in vitro using the four-drug regimen. Transfection with viral kinase cDNA increased cellular sensitivity to antiviral therapy.Conclusions: EBV+ PCNS-PTLD expressed lytic kinases and therapy with AZT, GCV, rituximab and dexamethasone provided durable responses. Induction of the lytic protein expression and increased cellular sensitivity to antiviral therapy after transfection with viral kinase cDNA provides a mechanistic rationale for our approach. Clin Cancer Res; 24(14); 3273-81. ©2018 AACR.

Novel therapies for malignant gliomas.

The impact of cytotoxic therapies on the outcome of glioblastoma has been modest thus far. Yet it is clear that subsets of high-grade gliomas exist that are sensitive to treatment. Patients deemed resistant to the current standard approach may be selected for alternative therapies, thereby avoiding treatment toxicity from an ineffective treatment. The future of novel therapies lies in our understanding of the molecular biology of gliomas and their stem cells. Not only will this drive the development of new agents, it will also lead to tailored therapies for specific tumors. Yet much research is still needed at all levels, from the identification of molecular markers to the development and application of novel therapeutics.

Chemotherapy and cerebral metastases: misperception or reality?

Cerebral metastases remain a common complication among patients with cancer. Surgery and radiotherapy remain the principal therapeutic interventions. In contrast, the benefit of chemotherapy has long been viewed with skepticism. Nonetheless, as survival in cancer patients improves and the incidence of cerebral metastases increases, so does the demand for effective therapies. It is now recognized that the blood-brain barrier within metastases is permeable and thus allows entry of otherwise excluded drugs. Limited data have suggested that cerebral metastases have modest sensitivity to chemotherapy. Furthermore, novel agents and delivery strategies have been developed to facilitate central nervous system penetration. Nonetheless, data are limited by methodological flaws, including heterogeneous inclusion criteria, small sample sizes, lack of randomization, and inconsistencies in defined end points and response assessment criteria. Well-designed clinical trials are needed to address the effect of chemotherapy. Acceptable control arms must be established to measure the effect of chemotherapies. Standardized response criteria and disease-specific studies are essential.

Clinical implications of status epilepticus in patients with neoplasms.

OBJECTIVES: To elucidate factors that contribute to the development of status epilepticus (SE) and determine prognostic factors and the impact on 30-day survival. DESIGN: Retrospective review of medical records. SETTING: University of Virginia Health System. Patients Thirty-five patients with SE secondary to a tumor, either primary or systemic, or its treatment. MAIN OUTCOME MEASURES: Seizure control, 30-day mortality, and overall survival. RESULTS: Status epilepticus most commonly occurred at tumor presentation or progression and was controlled in all cases. Thirty-day mortality was 23%. Patients with systemic cancer were at higher risk of death, although they were older and had more acute comorbidities. Age, tumor type, status of tumor at time of event, history of epilepsy, and status type were not predictive of mortality. Age was associated with a higher rate of nursing home placement and shorter overall survival. Overall survival was determined by underlying tumor. CONCLUSIONS: Status epilepticus in patients with cancer is responsive to therapy. Workup of underlying causes is indicated, even in the presence of subtherapeutic antiepileptic drug levels, because coexistent conditions contributing to the development of SE may be present. In those with known cancer, brain imaging should be performed because SE usually occurs in the setting of tumor progression or new metastases.

Brain tumor imaging and cancer management: the neuro-oncologists perspective.

Brain tumors remain a significant cause of morbidity and mortality and are often refractory to treatment. Neuroimaging, in particular magnetic resonance imaging (MRI) and associated techniques, has become an important tool for the neuro-oncologist in the management of brain tumors. Magnetic resonance imaging is the most sensitive method to demonstrate the presence of a mass in the brain and can often narrow the differential diagnosis with nonneoplastic lesions such as cerebral abscess and subacute infarction. Once the diagnosis has been confirmed, MRI is essential for initial treatment planning, including surgical resection and radiation therapy. In selected patients, serial MRI will also be necessary to evaluate for response during adjuvant chemotherapy and to monitor for treatment-induced toxicity. New magnetic resonance techniques such as magnetic resonance spectroscopy, diffusion-weighted imaging, and perfusion-based imaging methods will also be discussed where applicable.

Phase II multicenter study of gene-mediated cytotoxic immunotherapy as adjuvant to surgical resection for newly diagnosed malignant glioma.

BACKGROUND: Despite aggressive standard of care (SOC) treatment, survival of malignant gliomas remains very poor. This Phase II, prospective, matched controlled, multicenter trial was conducted to assess the safety and efficacy of aglatimagene besadenovec (AdV-tk) plus valacyclovir (gene-mediated cytotoxic immunotherapy [GMCI]) in combination with SOC for newly diagnosed malignant glioma patients. METHODS: Treatment cohort patients received SOC + GMCI and were enrolled at 4 institutions from 2006 to 2010. The preplanned, matched-control cohort included all concurrent patients meeting protocol criteria and SOC at a fifth institution. AdV-tk was administered at surgery followed by SOC radiation and temozolomide. Subset analyses were preplanned, based on prognostic factors: pathological diagnosis (glioblastoma vs others) and extent of resection. RESULTS: Forty-eight patients completed SOC + GMCI, and 134 met control cohort criteria. Median overall survival (OS) was 17.1 months for GMCI + SOC versus 13.5 months for SOC alone (P = .0417). Survival at 1, 2, and 3 years was 67%, 35%, and 19% versus 57%, 22%, and 8%, respectively. The greatest benefit was observed in gross total resection patients: median OS of 25 versus 16.9 months (P = .0492); 1, 2, and 3-year survival of 90%, 53%, and 32% versus 64%, 28% and 6%, respectively. There were no dose-limiting toxicities; fever, fatigue, and headache were the most common GMCI-related symptoms. CONCLUSIONS: GMCI can be safely combined with SOC in newly diagnosed malignant gliomas. Survival outcomes were most notably improved in patients with minimal residual disease after gross total resection. These data should help guide future immunotherapy studies and strongly support further evaluation of GMCI for malignant gliomas. CLINICAL TRIAL REGISTRY: ClinicalTrials.gov NCT00589875.

Low-grade gliomas: an update on pathology and therapy.

Low-grade gliomas (LGG) are not benign neoplasms. Patients with LGG eventually die as a consequence of this disease. Although the survival of patients with LGG is better than that of patients with higher-grade tumours, many of the treatments can produce or contribute to chronic impairment, particularly radiotherapy. Chemotherapy has emerged as a promising therapy, although definitive findings are awaited. Breakthroughs in molecular biology have improved our understanding of tumours and have led to the development of novel treatments and better prognoses. Ongoing clinical trials will help to elucidate the optimum management of patients with LGG.

Clinical practice experience with NovoTTF-100A™ system for glioblastoma: The Patient Registry Dataset (PRiDe).

Recurrent glioblastoma multiforme (GBM) is a highly aggressive cancer with poor prognosis, and an overall survival of 6 to 7 months with optimal therapies. The NovoTTF-100A™ System is a novel antimitotic cancer therapy recently approved for the treatment of recurrent GBM, based on phase III (EF-11) trial results. The Patient Registry Dataset (PRiDe) is a post-marketing registry of all recurrent GBM patients who received NovoTTF Therapy in a real-world, clinical practice setting in the United States between 2011 and 2013. Data were collected from all adult patients with recurrent GBM who began commercial NovoTTF Therapy in the United States between October 2011 and November 2013. All patients provided written consent before treatment was started. Overall survival (OS) curves were constructed for PRiDe using the Kaplan-Meier method. Median OS in PRiDe was compared for patients stratified by average daily compliance (≥75% v<75% per day) and other prognostic variables. Adverse events were also evaluated. Data from 457 recurrent GBM patients who received NovoTTF Therapy in 91 US cancer centers were analyzed. More patients in PRiDe than the EF-11 trial received NovoTTF Therapy for first recurrence (33% v 9%) and had received prior bevacizumab therapy (55.1% v 19%). Median OS was significantly longer with NovoTTF Therapy in clinical practice (PRiDe data set) than in the EF-11 trial (9.6 v 6.6 months; HR, 0.66; 95% CI, 0.05 to 0.86, P = .0003). One- and 2-year OS rates were more than double for NovoTTF Therapy patients in PRiDe than in the EF-11 trial (1-year: 44% v 20%; 2-year: 30% v 9%). First and second versus third and subsequent recurrences, high Karnofsky performance status (KPS), and no prior bevacizumab use were favorable prognostic factors. No unexpected adverse events were detected in PRiDe. As in the EF-11 trial, the most frequent adverse events were mild to moderate skin reactions associated with application of the NovoTTF Therapy transducer arrays. Results from PRiDe, together with those previously reported in the EF-11 trial, indicate that NovoTTF Therapy offers clinical benefit to patients with recurrent GBM. NovoTTF Therapy has high patient tolerability and favorable safety profile in the real-world, clinical practice setting.

Radiation necrosis mimicking rapid intracranial progression of melanoma metastasis in two patients treated with vemurafenib.

Optimal treatment of metastases to the central nervous system (CNS) in patients with malignant melanoma remains a clinical challenge. In particular, for patients with BRAF-mutant melanoma and CNS metastases, much remains unknown about the safety and efficacy of the novel BRAF-targeted agents when administered in close sequence with radiation. We report two cases of rapid development of CNS radiation necrosis in patients with metastatic melanoma treated with the BRAF inhibitor, vemurafenib, closely sequenced with stereotactic radiosurgery or fractionated stereotactic radiation therapy. In the absence of prospective safety data from clinical trials, we advise vigilance in monitoring patients with BRAF-mutant melanoma whose treatment plan includes CNS radiation and vemurafenib and caution when assessing treatment response within the CNS in these patients.