Steven I. Robinson

Adult Ewing Sarcoma: Survival and Local Control Outcomes in 102 Patients with Localized Disease

Objectives. To assess the clinical features and local control (LC) outcomes in adult patients with localized Ewing Sarcoma (ES). Methods. The records of 102 ES patients with localized disease ≥18 years of age seen from 1977 to 2007 were reviewed. Factors relevant to prognosis, survival, and LC were analyzed. Results. The 5-year overall survival (OS) and event-free survival (EFS) were 60% and 52%, respectively, for the entire cohort. Treatment era (1977–1992 versus 1993–2007) remained an independent prognostic factor for OS on multivariate analysis, with improved outcomes observed in the 1993–2007 era (P = 0.02). The 5-year OS and EFS for the 1993–2007 era were 73% and 60%, respectively. Ifosfamide and etoposide based chemotherapy and surgery were more routinely used in the 1993–2007 era (P < 0.01). The 5-year local failure rate (LFR) was 14%, with a 5-year LFR of 18% for surgery, 33% for radiation, and 0% for combined surgery and radiation in the 1993–2007 era (P = 0.17). Conclusion. Modern survival outcomes for adults with localized ES are similar to multi-institutional results in children. This improvement over time is associated with treatment intensification with chemotherapy and increased use of surgery. Aggressive LC (combined surgery and radiation) may improve outcomes in poor prognosis patients.

Clinical activity of pazopanib in metastatic extraosseous Ewing sarcoma

We report a response to pazopanib in a 69-year-old man with heavily pre-treated metastatic extraosseous Ewing sarcoma in addition to molecular profiling of his tumor. To our knowledge, this case is the earliest to demonstrate activity of an oral multi-targeted kinase inhibitor in Ewing sarcoma. This case provides rationale for adding a Ewing sarcoma arm to SARC024, a phase II study of regorafenib, another multi-targeted kinase inhibitor, in patients with liposarcoma, osteosarcoma and Ewing and Ewing-like sarcomas (NCT02048371). This national multi-institutional study is ongoing.

Potential and clinical translation of oncolytic measles viruses

ABSTRACT Introduction: Oncolytic viruses represent a novel treatment modality that is unencumbered by the standard resistance mechanisms limiting the therapeutic efficacy of conventional antineoplastic agents. Attenuated engineered measles virus strains derived from the Edmonston vaccine lineage have undergone extensive preclinical evaluation with significant antitumor activity observed in a broad range of preclinical tumoral models. These have laid the foundation for several clinical trials in both solid and hematologic malignancies, which have demonstrated safety, biologic activity and the ability to elicit antitumor immune responses. Areas covered: This review examines the published preclinical data which supported the clinical translation of this therapeutic platform, reviews the available clinical trial data and expands on ongoing phase II testing. It also looks at approaches to optimize clinical applicability and offers future perspectives. Expert opinion: Reverse genetic engineering has allowed the generation of oncolytic MV strains retargeted to increase viral tumor specificity, or armed with therapeutic and immunomodulatory genes in order to enhance anti-tumor efficacy. Continuous efforts focusing on exploring methods to overcome resistance pathways and determining optimal combinatorial strategies will facilitate further development of this encouraging antitumor strategy.

Adolescent and Young Adult Oncology, Version 2.2018, NCCN Clinical Practice Guidelines in Oncology

This selection from the NCCN Guidelines for Adolescent and Young Adult (AYA) Oncology focuses on treatment and management considerations for AYA patients with cancer. Compared with older adults with cancer, AYA patients have unique needs regarding treatment, fertility counseling, psychosocial and behavioral issues, and supportive care services. The complete version of the NCCN Guidelines for AYA Oncology addresses additional aspects of caring for AYA patients, including risk factors, screening, diagnosis, and survivorship.

Experience with precision genomics and tumor board, indicates frequent target identification, but barriers to delivery

Background The ability to analyze the genomics of malignancies has opened up new possibilities for off-label targeted therapy in cancers that are refractory to standard therapy. At Mayo Clinic these efforts are organized through the Center for Individualized Medicine (CIM). Results Prior to GTB, datasets were analyzed and integrated by a team of bioinformaticians and cancer biologists. Therapeutically actionable mutations were identified in 65% (92/141) of the patients tested with 32% (29/92) receiving genomically targeted therapy with FDA approved drugs or in an independent clinical trial with 45% (13/29) responding. Standard of care (SOC) options were continued by 15% (14/92) of patients tested before exhausting SOC options, with 71% (10/14) responding to treatment. Over 35% (34/92) of patients with actionable targets were not treated with 65% (22/34) choosing comfort measures or passing away. Materials and Methods Patients (N = 165) were referred to the CIM Clinic between October 2012 and December 2015. All patients received clinical genomic panel testing with selected subsets receiving array comparative genomic hybridization and clinical whole exome sequencing to complement and validate panel findings. A genomic tumor board (GTB) reviewed results and, when possible, developed treatment recommendations. Conclusions Treatment decisions driven by tumor genomic analysis can lead to significant clinical benefit in a minority of patients. The success of genomically driven therapy depends both on access to drugs and robustness of bioinformatics analysis. While novel clinical trial designs are increasing the utility of genomic testing, robust data sharing of outcomes is needed to optimize clinical benefit for all patients.

Incidence, Characteristics, and Implications of Seizures in Patients With Glioblastoma:

Background: Seizures in patients with glioblastoma are associated with worse quality of life. However, their incidence, clinical characteristics, and prognostic implications are less well characterized. Objective: This study was undertaken to provide a contemporary experience along with benchmark data relevant to the above in patients with glioblastoma. It also sought to reexplore improved survival with seizures, as observed by others. Methods: In this single-institution study, patients with glioblastoma from 2010 through 2014 had their medical records reviewed in detail. Results: Among 122 patients, 58 (48%) had a seizure history. Of these, 67% had more than 1, 41% had generalized seizures, and most received antiseizure medication (most commonly levetiracetam). The median survival for patients with seizures was 1.66 years and 0.87 years for those without (hazard ratio for risk of death with seizures: 0.72; 95% confidence interval: 0.43, 1.21; P = .22 by the log-rank test). Conclusion: Seizures are common in patients with glioblastoma and, in contrast to earlier reports, are not associated with a statistically significant improvement in survival.

Adult Ewing sarcoma: survival and local control outcomes in 36 patients with metastatic disease.

Objectives:To assess the clinical features and outcomes in adult patients with metastatic Ewing sarcoma (ES). Methods:The records of 36 ES patients with metastatic disease ≥18 years seen from 1977 to 2007 at the Mayo Clinic were studied retrospectively. Factors relevant to prognosis, survival, and local control (LC) were analyzed. Results:The 4-year overall survival (OS) and event-free survival (EFS) rates were 20% and 11%, respectively. Patients treated from 1993 to 2007 had significantly improved outcomes compared with those treated from 1977 to 1992: 4-year OS and EFS of 31% and 16%, respectively, versus 0% (P=0.01). Primary tumor (P=0.005 and 0.04) and metastatic sites (P=0.05) were independent EFS prognostic factors. Four patients (11%) received surgery, 18 (50%) radiation therapy (RT), 4 (11%) surgery+radiation therapy (S+RT), and 10 (28%) received no LC. The 4-year EFS rates were 0% for surgery, 21% for RT, 0% for S+RT, and 0% for no LC (P=0.0001). OS in patients who received vincristine, doxorubicin, and cyclophosphamide alternating with ifosphamide and etoposide (VDC/IE) chemotherapy was improved (P=0.04). Relapses were documented in 18 patients (excluding patients who received no LC). In total, 44% of patients had all of their metastatic site(s) treated. Patients who received treatment to all extrapulmonary metastases had significantly improved outcomes compared with those who did not receive treatment to all sites: 4-year OS and EFS of 33% and 11%, respectively, versus 0% (P=0.04 and 0.02). Conclusions:Our results suggest outcomes for adult patients with metastatic ES are similar to pediatric cohorts in the modern era. VDC/IE chemotherapy and treatment to all metastatic lesions is associated with improved outcomes.

Can sorafenib cause hypothyroidism

Sunitinib, a multiple tyrosine kinase inhibitor with antiangiogenic properties has been reported to be associated with hypothyroidism in 57-85% of treated patients, though the mechanism is unclear 13. Sunitinib and imatinib have even been reported to cause hypothyroidism in patients already on replacement levothyroxine for prior thyroidectomy 4,5. We report a 53-year-old woman with non-functional metastatic islet cell carcinoma treated with sorafenib, a novel multiple tyrosine kinase inhibitor, in the context of a IRB-approved clinical trial (MC044H), with resultant development of hypothyroidism. Our patient initially presented to our institution with a sudden exacerbation of a chronic non-specific epigastric pain. She was found to have metastatic pancreatic islet cell carcinoma with liver metastases. Due to lack of symptoms, she was observed for three years prior to initiation of therapy, which was done due to slow progression. She initially received gefitinib in a clinical trial, but progressed after 6 months. She subsequently enrolled in the trial using sorafenib (400 mg twice daily). The dose was reduced to 200 mg po BID due to epigastric discomfort. After one month at the reduced dose, she developed transient throat pain, followed by heat intolerance, palpitations and hair loss. Her thyroid stimulating hormone (TSH) level was suppressed to 0.02 mIU/L (0.3-5.0, see Table 1) One month later, the TSH was repeated and a total thyroxine checked, which was slightly elevated (though the patient was on estrogen replacement which can elevate total thyroxine levels 6). The only prior baseline value was a TSH of 2.6 mIU/L, drawn three years earlier. For the palpitations, she was placed on Journal of Chemotherapy Vol. 19 n. 3 (352-353) 2007

A Phase II Study of Tivozanib in Patients with Metastatic and Nonresectable Soft-Tissue Sarcomas

BACKGROUND Soft tissue sarcomas (STSs) overexpress vascular endothelial growth factors (VEGF) and VEGF-receptors (VEGFR) activation have been associated with tumor aggressiveness. Tivozanib is a potent small molecule tyrosine kinase inhibitor against VEGFR1-3, with activity against PDGFRα/β and cKIT. The primary endpoint of this study was progression free survival (PFS) rate at 16 weeks. Secondary end points were overall survival (OS), response rate, safety and correlative studies. PATIENTS AND METHODS A Simon two-stage phase II trial was performed using tivozanib given orally at 1.5 mg daily, 3 week on 1 week off on a 28 day cycle until disease progression or intolerable toxicity. RESULTS Fifty-eight patients were enrolled and treated with tivozanib. Leiomyosarcoma was the most common STS histological type in our cohort (47%) and 27 patients (46%) had received at least 3 lines of therapy prior to study entry. Up to 24 patients (41%) had prior VEGF targeted therapies. Partial response and stable disease were observed in 2 (3.6%) and 30 (54.5%) patients. The 16 week PFS rate was 36.4% [95% confidence interval (CI) 23.7-49.1] and a median PFS of 3.5 months (95% CI 1.8-3). Median OS observed was 12.2 months (95% CI 8.1-16.8). The most frequent all grade toxicities were fatigue (48.3%), hypertension (43.1%), nausea (31%) and diarrhea (27.6%). The most common grade three toxicity was hypertension (22.4%). Correlative studies demonstrate no correlation between the expression of VEGFR 1, 2 or 3, PDGFRα/β or FGF, and activity of tivozanib. CONCLUSION Tivozanib was well tolerated and showed antitumor activity with a promising median PFS and PFS rate at 4 months in a heavily pretreated population of metastatic STSs. Our results support further studies to assess the clinical efficacy of tivozanib in STS. CLINICAL TRIAL NUMBER NCT01782313.Background Soft tissue sarcomas (STSs) overexpress vascular endothelial growth factors (VEGF) and VEGF-receptors (VEGFR) activation have been associated with tumor aggressiveness. Tivozanib is a potent small molecule tyrosine kinase inhibitor against VEGFR1-3, with activity against PDGFRα/β and cKIT. The primary endpoint of this study was progression free survival (PFS) rate at 16 weeks. Secondary end points were overall survival (OS), response rate, safety and correlative studies. Patients and methods A Simon two-stage phase II trial was performed using tivozanib given orally at 1.5 mg daily, 3 week on 1 week off on a 28 day cycle until disease progression or intolerable toxicity. Results Fifty-eight patients were enrolled and treated with tivozanib. Leiomyosarcoma was the most common STS histological type in our cohort (47%) and 27 patients (46%) had received at least 3 lines of therapy prior to study entry. Up to 24 patients (41%) had prior VEGF targeted therapies. Partial response and stable disease were observed in 2 (3.6%) and 30 (54.5%) patients. The 16 week PFS rate was 36.4% [95% confidence interval (CI) 23.7-49.1] and a median PFS of 3.5 months (95% CI 1.8-3). Median OS observed was 12.2 months (95% CI 8.1-16.8). The most frequent all grade toxicities were fatigue (48.3%), hypertension (43.1%), nausea (31%) and diarrhea (27.6%). The most common grade three toxicity was hypertension (22.4%). Correlative studies demonstrate no correlation between the expression of VEGFR 1, 2 or 3, PDGFRα/β or FGF, and activity of tivozanib. Conclusion Tivozanib was well tolerated and showed antitumor activity with a promising median PFS and PFS rate at 4 months in a heavily pretreated population of metastatic STSs. Our results support further studies to assess the clinical efficacy of tivozanib in STS. Clinical Trial Number NCT01782313.

Pelvis Ewing sarcoma: Local control and survival in the modern era

Local control for Ewing sarcoma (ES) has improved in modern studies. However, it is unclear if these gains have also been achieved for pelvis tumors. The purpose of this study is to evaluate local control and survival in pelvis ES patients treated in the modern era.