Seema Nagpal, MD

All Publications

• A Phase I/II Trial of 5-Fraction Stereotactic Radiosurgery with 5-mm Margins with Concurrent Temozolomide in Newly Diagnosed Glioblastoma: Primary Outcomes. Neuro-oncology Azoulay, M., Chang, S. D., Gibbs, I. C., Hancock, S. L., Pollom, E. L., Harsh, G. R., Adler, J. R., Harrahar, C., Li, G., Hayden Gephart, M., Nagpal, S., Thomas, R. P., Recht, L. D., Jacobs, L. R., Modlin, L. A., Wynne, J., Seiger, K., Fujimoto, D., Usoz, M., von Eyben, R., Choi, C. Y., Soltys, S. G. 2020

  Abstract

  We sought to determine the maximum tolerated dose (MTD) of 5-fraction stereotactic radiosurgery (SRS) with 5-mm margins delivered with concurrent temozolomide in newly diagnosed glioblastoma.We enrolled adult patients with newly diagnosed glioblastoma to 5 days of SRS in a 3+3 design on 4 escalating dose levels: 25, 30, 35, and 40 Gy. Dose limiting toxicity (DLT) was defined as CTCAE Grade 3-5 acute or late CNS toxicity, including adverse radiation effect (ARE), the imaging correlate of radiation necrosis.From 2010 to 2015, 30 patients were enrolled. The median age was 66 years (range 51-86 years). The median target volume was 60 cm3 (range 14.7-137.3 cm3). DLT occurred in 2 patients: one for post-treatment cerebral edema and progressive disease at 3 weeks (Grade 4, Dose 40 Gy); another patient died 1.5 weeks following SRS from post-operative complications (Grade 5, Dose 40 Gy). Late grade 1-2 ARE occurred in 8 patients at a median of 7.6 months (range 3.2-12.6 months). No grade 3-5 ARE occurred. With a median follow-up of 13.8 months (range 1.7-64.4 months), the median survival times were: PFS 8.2 months (95%CI 4.6-10.5), OS 14.8 months (95%CI 10.9-19.9), MGMT hypermethylated 19.9 months (95%CI 10.5-33.5) vs. 11.3 months (95%CI 8.9-17.6) for no/unknown hypermethylation (p=0.03), and 27.2 months (95%CI 11.2-48.3) if late ARE occurred vs. 11.7 months (95%CI 8.9-17.6) for no ARE (p=0.08).The per-protocol MTD of 5-fraction SRS with 5-mm margins with concurrent temozolomide was 40 Gy in 5 fractions. ARE was limited to grade 1-2 and did not statistically impact survival.

  View details for DOI 10.1093/neuonc/noaa019

  View details for PubMedID 32002547

• Macrophage exclusion after radiation therapy (MERT): A new and effective way to increase the therapeutic ratio of radiotherapy. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology Brown, J. M., Thomas, R., Nagpal, S., Recht, L. 2019; 144: 159–64

  Abstract

  Here we review a variety of preclinical studies and a first-in-human clinical trial of newly diagnosed glioblastoma (GBM) patients that have investigated the significance of the influx of tumor associated macrophages (TAMs) into tumors after irradiation. We summarize the effects on the response of the tumors and normal tissues to radiation of various agents that either reduce the influx of TAMs into tumors after radiation or change their M1/M2 polarization. The studies show that following irradiation there is an accumulation of bone marrow derived TAMs in the irradiated tumors. These TAMs stimulate the resumption of blood flow in the irradiated tumors thereby promoting recurrence of the tumors. A key mechanism for this accumulation of TAMs is driven by the SDF-1/CXCR4 chemokine pathway though other pathways could also be involved for some tumors. Blocking this pathway to prevent the TAM accumulation in the tumors both enhances tumor response to radiation and protects irradiated tissues. A clinical trial in which the CXCR4 antagonist plerixafor was added to standard therapy of glioblastoma validated the preclinical findings by demonstrating i) reduced blood flow in the irradiated site, and ii) significantly improved tumor local control compared to GBM patients not treated with plerixafor. We conclude that macrophage exclusion after radiation therapy (MERT) is an effective way both to enhance the tumor response to radiation and to protect the irradiated normal tissues. Further clinical trials are warranted.

  View details for DOI 10.1016/j.radonc.2019.11.020

  View details for PubMedID 31812931

• Professor Seema Nagpal: which one should be given the priority, radiation or drug? ANNALS OF TRANSLATIONAL MEDICINE Zhou, M., Zhou, A., Nagpal, S. 2019; 7 (22)

  View details for DOI 10.21037/atm.2019.09.165

  View details for Web of Science ID 000500459400098

• INO-5401 and INO-9012 delivered by electroporation (EP) in combination with cemiplimab (REGN2810) in newly-diagnosed glioblastoma (GBM) (NCT03491683) Reardon, D., Nagpal, S., Soltys, S., Brem, S., Omuro, A., De La Fuente, M., Bredlau, A., Lowy, I., Fury, M., Morrow, M., Kraynyak, K., McMullan, T., Santo, A. L., Sacchetta, B., Skolnik, J. AMER ASSOC CANCER RESEARCH. 2019

  View details for DOI 10.1158/1538-7445.AM2019-CT114

  View details for Web of Science ID 000488129900102

• BPM31510 exploits differential redox vulnerabilities between normal and glioblastoma cells to mediate its anti-cancer effect Sun, J., Nagpal, S., Patel, C., Merchant, M., Jang, T., Diers, A. R., Kazerounian, S., Gesta, S., Narain, N. R., Sarangarajan, R., Recht, L. AMER ASSOC CANCER RESEARCH. 2019

  View details for DOI 10.1158/1538-7445.AM2019-3608

  View details for Web of Science ID 000488279403015

• Osimertinib for EGFR-Mutant Lung Cancer with Brain Metastases: Results from a Single-Center Retrospective Study ONCOLOGIST Xie, L., Nagpal, S., Wakelee, H. A., Li, G., Soltys, S. G., Neal, J. W. 2019; 24 (6): 836–43

  View details for DOI 10.1634/theoncologist.2018-0264

  View details for Web of Science ID 000471906300044

• Adverse Radiation Effect and Disease Control in Patients Undergoing Stereotactic Radiosurgery and Immune Checkpoint Inhibitor Therapy for Brain Metastases WORLD NEUROSURGERY Koenig, J. L., Shi, S., Sborov, K., Gensheimer, M. F., Le, G., Nagpal, S., Chang, S. D., Gibbs, I. C., Soltys, S. G., Pollom, E. L. 2019; 126: E1399–E1411

  View details for DOI 10.1016/j.wneu.2019.03.110

  View details for Web of Science ID 000469222400177

• To Biopsy or Not to Biopsy? A case of primary intramedullary spinal cord lymphoma presenting as longitudinally extensive transverse myelitis within cervical cord Satyanarayan, S., Rizvi, A., Nagpal, S. LIPPINCOTT WILLIAMS & WILKINS. 2019

  View details for Web of Science ID 000475965901426

• Adverse Radiation Effect and Disease Control in Patients Undergoing Stereotactic Radiosurgery and Immune Checkpoint Inhibitor Therapy for Brain Metastases. World neurosurgery Koenig, J. L., Shi, S., Sborov, K., Gensheimer, M. F., Li, G., Nagpal, S., Chang, S. D., Gibbs, I. C., Soltys, S. G., Pollom, E. L. 2019

  Abstract

  BACKGROUND: Immune checkpoint inhibitors (ICIs) and stereotactic radiosurgery (SRS) are increasingly used together to manage brain metastases (BMs). We assessed adverse radiation effect, disease control, and overall survival in patients with BMs who received SRS with anti-CTLA-4 and/or anti-PD-1/PD-L1 therapies.METHODS: We retrospectively reviewed the records of patients with intact or resected BMs treated with SRS and ICIs within 5 months of SRS between 2010 and 2018. Patients were defined as receiving 'concurrent' SRS and ICI if a dose of ICI was given within 4 weeks of SRS. Local failure (LF), distant intracranial failure (DIF), extracranial failure (EF), and adverse radiation effect (ARE) were assessed using cumulative incidence rates and competing risk regressions with death as a competing risk. Overall survival was assessed using the Kaplan-Meier method and Cox proportional hazards models.RESULTS: A total of 97 patients with 580 BMs were included in our analysis. Competing risk analyses demonstrated that concurrent SRS-ICI therapy is associated with higher rates of ARE (6.4% vs 2.0% at 1 year; multivariable HR 4.47; 95% CI, 1.57-12.73; p=0.005), lower rates of EF (69.7% vs 80.8% at 1 year; multivariable HR 0.60; 95% CI, 0.42-0.87; p=0.007), and better overall survival (48.6% vs 25.4% at 1 year; multivariable HR 0.57; 95% CI, 0.33-0.99; p=0.044) as compared to non-concurrent therapy. SRS-ICI timing was not associated with LF or DIF.CONCLUSIONS: Concurrent SRS-ICI therapy has a tolerable adverse event profile and may improve extracranial disease control and overall survival, supporting concurrent use in the management of BMs.

  View details for PubMedID 30902777

• Current State of Immunotherapy for Treatment of Glioblastoma. Current treatment options in oncology McGranahan, T., Therkelsen, K. E., Ahmad, S., Nagpal, S. 2019; 20 (3): 24

  Abstract

  OPINION STATEMENT: At this time, there are no FDA-approved immune therapies for glioblastoma (GBM) despite many unique therapies currently in clinical trials. GBM is a highly immunosuppressive tumor and there are limitations to a safe immune response in the central nervous system. To date, there have been several failures of phase 3 immune therapy clinical trials in GBM. These trials have targeted single components of an antitumor immune response. Learning from these failures, the future of immunotherapy for GBM appears most hopeful for combination of immune therapies to overcome the profound immunosuppression of this disease. Understanding biomarkers for appropriate patient selection as well as tumor progression are necessary for implementation of immunotherapy for GBM.

  View details for PubMedID 30790064

• Nodular Leptomeningeal Disease - A Distinct Pattern of Recurrence After Post-Resection Stereotactic Radiosurgery for Brain Metastases: A Multi-Institutional Study of Inter-Observer Reliability. International journal of radiation oncology, biology, physics Turner, B. E., Prabhu, R. S., Burri, S. H., Brown, P. D., Pollom, E. L., Milano, M. T., Weiss, S. E., Iv, M., Fischbein, N., Soliman, H., Lo, S. S., Chao, S. T., Cox, B. W., Murphy, J. D., Li, G., Gephart, M. H., Nagpal, S., Atalar, B., Azoulay, M., Thomas, R., Tillman, G., Durkee, B. Y., Shah, J. L., Soltys, S. G. 2019

  Abstract

  For brain metastases, surgical resection with postoperative stereotactic radiosurgery (SRS) is an emerging standard of care. Postoperative cavity SRS is associated with a specific, under-recognized pattern of intracranial recurrence, herein termed nodular leptomeningeal disease (nLMD), which is distinct from classical leptomeningeal disease (cLMD). We hypothesized that there is poor consensus regarding the definition of LMD, and that a formal, self-guided training module will improve inter-rater reliability (IRR) and validity in diagnosing LMD.Twenty-two physicians at 16 institutions, including 15 physicians with central nervous system (CNS) expertise, completed a two-phase survey that included MRI imaging and treatment information for 30 patients. In the "pre-training" phase, physicians labeled cases using 3 patterns of recurrence commonly reported in prospective studies: local recurrence (LR), distant parenchymal recurrence (DR), and LMD. After a self-directed training module, participating physicians completed the "post-training" phase and relabeled the 30 cases using the 4 following labels: LR, DR, cLMD, nLMD.Inter-rater reliability (IRR) increased 34% after training (Fleiss' Kappa K=0.41 to K=0.55, p<0.001). IRR increased most among non-CNS specialists (+58%, p<0.001). Prior to training, IRR was lowest for LMD (K=0.33). After training, IRR increased across all recurrence subgroups and increased most for LMD (+67%). After training, ≥27% of cases initially labeled LR or DR were later recognized as nLMD.This study highlights the large degree of inconsistency among clinicians in recognizing nLMD. Our findings demonstrate that a brief self-guided training module distinguishing nLMD can significantly improve IRR across all patterns of recurrence, and particularly in nLMD. To optimize outcomes reporting, prospective trials in brain metastases should incorporate central imaging review and investigator training.

  View details for DOI 10.1016/j.ijrobp.2019.10.002

  View details for PubMedID 31605786

• Macrophage Exclusion after Radiation Therapy (MERT): A First in Human Phase I/II Trial using a CXCR4 Inhibitor in Glioblastoma. Clinical cancer research : an official journal of the American Association for Cancer Research Thomas, R. P., Nagpal, S., Iv, M., Soltys, S. G., Bertrand, S., Pelpola, J. S., Ball, R. L., Yang, J., Sundaram, V., Lavezo, J. L., Born, D. E., Vogel, H., Brown, J. M., Recht, L. 2019

  Abstract

  Preclinical studies have demonstrated that post-irradiation tumor revascularization is dependent on a stromal cell-derived factor-1 (SDF-1)/C-X-C chemokine receptor type 4 (CXCR4)-driven process in which myeloid cells are recruited from bone marrow. Blocking this axis results in survival improvement in preclinical models of solid tumors, including glioblastoma (GBM). We conducted a phase I/II study to determine the safety and efficacy of Macrophage Exclusion after Radiation Therapy (MERT) using the reversible CXCR4 inhibitor plerixafor in newly diagnosed glioblastoma patients.We enrolled 9 patients to the phase I study and an additional 20 patients to phase II using a modified toxicity probability interval (mTPI) design. Plerixafor was continuously infused intravenously via PICC line for four consecutive weeks beginning at day 35 of conventional treatment with concurrent chemo-radiation. Blood serum samples were obtained for pharmacokinetic analysis. Additional studies included relative cerebral blood volume (rCBV) analysis using MRI and histopathology analysis of recurrent tumors.Plerixafor was well tolerated with no drug-attributable grade 3 toxicities observed. At the maximum dose of 400 µg/kg/day, biomarker analysis found suprathreshold plerixafor serum levels and an increase in plasma SDF-1 levels. Median overall survival was 21.3 months (95% Confidence Interval (CI) 15.9, NA) with a progression-free survival of 14.5 months (95% CI 11.8, NA). MRI and histopathology support the mechanism of action to inhibit post-irradiation tumor revascularization.Infusion of the CXCR4 inhibitor plerixafor was well tolerated as an adjunct to standard chemo-irradiation in newly diagnosed GBM patients and improves local control of tumor recurrences.

  View details for DOI 10.1158/1078-0432.CCR-19-1421

  View details for PubMedID 31537527

• Case closed: another prophylactic cranial irradiation trial for stage 3 non-small cell lung cancer fails to improve overall survival ANNALS OF TRANSLATIONAL MEDICINE Moghavem, N., Wakelee, H. A., Nagpal, S. 2018; 6

  View details for DOI 10.21037/atm.2018.12.24

  View details for Web of Science ID 000454556000033

• Central Nervous System Lymphoma in a Patient with Chronic Lymphocytic Leukemia: A Case Report and Literature Review. Cureus Albakr, A., Alhothali, W., Samghabadi, P., Maeda, L., Nagpal, S., Ajlan, A. 2018; 10 (11): e3660

  Abstract

  Chronic lymphocytic leukemia (CLL) is the most common type of leukemia that affects older adults in the Western world. Symptomatic nervous system invasion in undiagnosed CLL is rare, poorly understood, challenging to treat, and associated with decreased survival. The average survival of CLL patients with central nervous system (CNS) involvement is 3.79 years as compared to six years in CLL patients without CNS involvement. Autopsy studies demonstrated ahigh incidence of undiagnosed CLL with CNS involvement, suggesting that CNS involvement is either underdiagnosed or subclinical. Although the most common site of CNS involvement is the leptomeninges, our case demonstrates an extremely rare form of CNS diffuse large B-cell parenchymal involvement in a patient with a concurrent diagnosis of systemic CLL.

  View details for PubMedID 30755837

• Developing a standardized process for oral chemotherapy management for neuro-oncology. McGranahan, T., Gershon, M., Pena, J., Bains, C., Van Meter, M., Salas, S., Nagpal, S. AMER SOC CLINICAL ONCOLOGY. 2018

  View details for DOI 10.1200/JCO.2018.36.30_suppl.258

  View details for Web of Science ID 000464875300252

• A Diffuse Leptomeningeal Glioneuronal Tumor Without Diffuse Leptomeningeal Involvement: Detailed Molecular and Clinical Characterization JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY Kung, J. H., Buckley, A. F., Nagpal, S., Fischbein, N., Peters, K. B. 2018; 77 (9): 751–56

  Abstract

  Prior to their provisional WHO classification as a distinct entity in 2016, diffuse leptomeningeal glioneuronal tumors (DLGNT) were often regarded as diffuse leptomeningeal presentations of oligodendrogliomas or extraventricular neurocytomas. Their classification as a distinct entity partly relies on their pattern of growth, but DLGNTs without radiological leptomeningeal involvement have been described. In a patient with a DLGNT of the spinal cord without evidence of leptomeningeal involvement, we review in depth the clinical course and the histologic and molecular features of the neoplasm, in the context of other reported cases without diffuse leptomeningeal involvement. Our findings highlight the advantages of molecular analysis in making accurate diagnoses on small spinal tissue samples and underline the need for more long-term clinical follow-up of these rare neoplasms to inform treatment decisions.

  View details for PubMedID 29931222

• BPM 31510, a clinical stage metabolic modulator, demonstrates therapeutic efficacy in glioblastoma models of temozolomide chemosensitive and resistance by targeting mitochondrial function Dadali, T., Kulkarni, S., Ng, R., Awate, P., Mogre, S., Diers, A. R., Jang, T., Merchant, M., Sun, J., Gesta, S., Thapa, K., Nagpal, S., Recht, L., Narain, N. R., Sarangarajan, R. AMER ASSOC CANCER RESEARCH. 2018

  View details for DOI 10.1158/1538-7445.AM2018-873

  View details for Web of Science ID 000468818902374

• Recurrently Mutated Genes Differ between Leptomeningeal and Solid Lung Cancer Brain Metastases. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer Li, Y., Liu, B., Connolly, I. D., Kakusa, B. W., Pan, W., Nagpal, S., Montgomery, S. B., Hayden Gephart, M. 2018

  Abstract

  When compared with solid brain metastases from NSCLC, leptomeningeal disease (LMD) has unique growth patterns and is rapidly fatal. Patients with LMD do not undergo surgical resection, limiting the tissue available for scientific research. In this study we performed whole exome sequencing on eight samples of LMD to identify somatic mutations and compared the results with those for 26 solid brain metastases. We found that taste 2 receptor member 31 gene (TAS2R31) and phosphodiesterase 4D interacting protein gene (PDE4DIP) were recurrently mutated among LMD samples, suggesting involvement in LMD progression. Together with a retrospective review of the charts of an additional 44 patients with NSCLC LMD, we discovered a surprisingly low number of KRAS mutations (n= 4 [7.7%]) but a high number of EGFR mutations (n= 33 [63.5%]). The median interval for development of LMD from NSCLC was shorter in patients with mutant EGFR (16.3 months) than in patients with wild-type EGFR (23.9 months) (p= 0.017). Targeted analysis of recurrent mutations thus presents a useful complement to the existing diagnostic tool kit, and correlations of EGFR in LMD and KRAS in solid metastases suggest that molecular distinctions or systemic treatment pressure underpin the differences in growth patterns within the brain.

  View details for PubMedID 29604399

• First-in-human intraoperative near-infrared fluorescence imaging of glioblastoma using cetuximab-IRDye800. Journal of neuro-oncology Miller, S. E., Tummers, W. S., Teraphongphom, N., van den Berg, N. S., Hasan, A., Ertsey, R. D., Nagpal, S., Recht, L. D., Plowey, E. D., Vogel, H., Harsh, G. R., Grant, G. A., Li, G. H., Rosenthal, E. L. 2018

  Abstract

  Maximizing extent of surgical resection with the least morbidity remains critical for survival in glioblastoma patients, and we hypothesize that it can be improved by enhancements in intraoperative tumor detection. In a clinical study, we determined if therapeutic antibodies could be repurposed for intraoperative imaging during resection.Fluorescently labeled cetuximab-IRDye800 was systemically administered to three patients 2 days prior to surgery. Near-infrared fluorescence imaging of tumor and histologically negative peri-tumoral tissue was performed intraoperatively and ex vivo. Fluorescence was measured as mean fluorescence intensity (MFI), and tumor-to-background ratios (TBRs) were calculated by comparing MFIs of tumor and histologically uninvolved tissue.The mean TBR was significantly higher in tumor tissue of contrast-enhancing (CE) tumors on preoperative imaging (4.0 ± 0.5) compared to non-CE tumors (1.2 ± 0.3; p = 0.02). The TBR was higher at a 100 mg dose than at 50 mg (4.3 vs. 3.6). The smallest detectable tumor volume in a closed-field setting was 70 mg with 50 mg of dye and 10 mg with 100 mg. On sections of paraffin embedded tissues, fluorescence positively correlated with histological evidence of tumor. Sensitivity and specificity of tumor fluorescence for viable tumor detection was calculated and fluorescence was found to be highly sensitive (73.0% for 50 mg dose, 98.2% for 100 mg dose) and specific (66.3% for 50 mg dose, 69.8% for 100 mg dose) for viable tumor tissue in CE tumors while normal peri-tumoral tissue showed minimal fluorescence.This first-in-human study demonstrates the feasibility and safety of antibody based imaging for CE glioblastomas.

  View details for PubMedID 29623552

• Osimertinib for EGFR-Mutant Lung Cancer with Brain Metastases: Results from a Single-Center Retrospective Study. The oncologist Xie, L., Nagpal, S., Wakelee, H. A., Li, G., Soltys, S. G., Neal, J. W. 2018

  Abstract

  Osimertinib is a third-generation tyrosine kinase inhibitor, initially approved for epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) with T790M acquired resistance, and now approved in the first-line setting. However, data supporting the use of osimertinib in untreated brain metastases are limited, although it has established central nervous system (CNS) activity. Our study compares the clinical outcomes of patients experiencing progressing brain metastases treated with cranial irradiation and osimertinib with those treated with osimertinib alone.Forty patients who were treated with osimertinib at the Stanford Cancer Center from November 2015 to December 2016 were identified by searching an electronic medical record database. Eleven patients had progressing brain metastases and did not receive radiation (group A), 9 patients had progressing brain metastases and received radiation when starting osimertinib (group B), and 20 patients had stable brain metastases at the time of initiating osimertinib (group C). Patient and disease characteristics, radiographic responses, and survival outcomes were evaluated retrospectively for the three groups.The CNS response rate was 32.3%. Median time to treatment failure (TTF), overall progression-free survival (PFS), and overall survival (OS) were 10.0 months (95% confidence interval [CI], 4.5-11.8), 8.8 months (95% CI, 6.2-12.1), and 16.2 months, respectively. Median TTF was 15.1 months for group A (95% CI, 1.7-28.5), 7.7 months for group B (95% CI, 0-15.5), and 10.7 months for group C (95% CI, 9.0-12.5). The median PFS was 8.8 months for group A (95% CI, 4.3-13.4), not reached for group B, and 8.4 months for group C (95% CI, 5.6-11.1). The median OS was not reached for group A and C, and was 16.2 months for group B. There was no apparent difference in TTF, PFS, or OS between the three groups.Receiving radiation prior to starting osimertinib for patients with progressing brain metastases did not prolong TTF, PFS, or OS in our series. To minimize the risks of radiation-related toxicity, delaying radiation could be considered for some patients with EGFR-mutant NSCLC with brain metastases who initially respond to osimertinib in the second-line setting.Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor recently approved for the first-line treatment of EGFR-mutant non-small cell lung cancer. Although it appears to have central nervous system (CNS) activity, most clinical trials have excluded patients with untreated, progressing brain metastases. This study included patients with stable and progressing CNS metastases treated with osimertinib and found no apparent differences in median time to treatment failure, time to progression, and overall survival in patients who received osimertinib alone compared with those who received osimertinib and radiosurgery. This may support a clinician's decision to defer radiation for selected patients with untreated brain metastases who are candidates for osimertinib therapy.

  View details for PubMedID 30126856

• Conditional Probability of Survival as a Proposed Endpoint for Future Single-Arm Clinical Trials in Glioblastoma Patel, C. B., Thomas, R. P., Nagpal, S., Recht, L. D. WILEY. 2017: S206–S207

  View details for Web of Science ID 000413198700445

• History and current state of immunotherapy in glioma and brain metastasis THERAPEUTIC ADVANCES IN MEDICAL ONCOLOGY McGranahan, T., Li, G., Nagpal, S. 2017; 9 (5): 347-368

  Abstract

  Malignant brain tumors such as glioblastoma (GBM) and brain metastasis have poor prognosis despite conventional therapies. Successful use of vaccines and checkpoint inhibitors in systemic malignancy has increased the hope that immune therapies could improve survival in patients with brain tumors. Manipulating the immune system to fight malignancy has a long history of both modest breakthroughs and pitfalls that should be considered when applying the current immunotherapy approaches to patients with brain tumors. Therapeutic vaccine trials for GBM date back to the mid 1900s and have taken many forms; from irradiated tumor lysate to cell transfer therapies and peptide vaccines. These therapies were generally well tolerated without significant autoimmune toxicity, however also did not demonstrate significant clinical benefit. In contrast, the newer checkpoint inhibitors have demonstrated durable benefit in some metastatic malignancies, accompanied by significant autoimmune toxicity. While this toxicity was not unexpected, it exceeded what was predicted from pre-clinical studies and in many ways was similar to the prior trials of immunostimulants. This review will discuss the history of these studies and demonstrate that the future use of immune therapy for brain tumors will likely need a personalized approach that balances autoimmune toxicity with the opportunity for significant survival benefit.

  View details for DOI 10.1177/1758834017693750

  View details for Web of Science ID 000400896200004

  View details for PubMedID 28529551

  View details for PubMedCentralID PMC5424864

• Phase 1/2 Trial of 5-Fraction Stereotactic Radiosurgery With 5-mm Margins With Concurrent and Adjuvant Temozolomide in Newly Diagnosed Supratentorial Glioblastoma: Health-Related Quality of Life Results. International journal of radiation oncology, biology, physics Pollom, E. L., Fujimoto, D., Wynne, J., Seiger, K., Modlin, L. A., Jacobs, L. R., Azoulay, M., von Eyben, R., Tupper, L., Gibbs, I. C., Hancock, S. L., Li, G., Chang, S. D., Adler, J. R., Harsh, G. R., Harraher, C., Nagpal, S., Thomas, R. P., Recht, L. D., Choi, C. Y., Soltys, S. G. 2017; 98 (1): 123-130

  Abstract

  We report a longitudinal assessment of health-related quality of life (HRQOL) in patients with glioblastoma (GBM) treated on a prospective dose escalation trial of 5-fraction stereotactic radiosurgery (25-40 Gy in 5 fractions) with concurrent and adjuvant temozolomide.HRQOL was assessed using the European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaire core-30 (QLQ-C30) general, the EORTC quality of life questionnaire-brain cancer specific module (QLQ-BN20), and the M.D. Anderson Symptom Inventory-Brain Tumor (MDASI-BT). Questionnaires were completed at baseline and at every follow-up visit after completion of radiosurgery. Changes from baseline for 9 predefined HRQOL measures (global quality of life, physical functioning, social functioning, emotional functioning, motor dysfunction, communication deficit, fatigue, insomnia, and future uncertainty) were calculated at every time point.With a median follow-up time of 10.4 months (range, 0.4-52 months), 139 total HRQOL questionnaires were completed by the 30 patients on trial. Compliance with HRQOL assessment was 76% at 12 months. Communication deficit significantly worsened over time, with a decline of 1.7 points per month (P=.008). No significant changes over time were detected in the other 8 scales of our primary analysis, including global quality of life. Although 8 patients (27%) experienced adverse radiation effects (ARE) on this dose escalation trial, it was not associated with a statistically significant decline in any of the primary HRQOL scales. Disease progression was associated with communication deficit, with patients experiencing an average worsening of 13.9 points per month after progression compared with 0.7 points per month before progression (P=.01).On this 5-fraction dose escalation protocol for newly diagnosed GBM, overall HRQOL remained stable and appears similar to historical controls of 30 fractions of radiation therapy. Tumor recurrence was associated with worsening communication deficit, and ARE did not correlate with a decline in HRQOL.

  View details for DOI 10.1016/j.ijrobp.2017.01.242

  View details for PubMedID 28586949

• A Neuro-oncologist's Perspective on Management of Brain Metastases in Patients with EGFR Mutant Non-small Cell Lung Cancer. Current treatment options in oncology McGranahan, T., Nagpal, S. 2017; 18 (4): 22-?

  Abstract

  Management of non-small cell lung cancer (NSCLC) with brain metastasis (BrM) has been revolutionized by identification of molecular subsets that have targetable oncogenes. Historically, survival for NSCLC with symptomatic BrM was weeks to months. Now, many patients are surviving years with limited data to guide treatment decisions. Tumors with activating mutations in epidermal growth factor receptor (EGFRact+) have a higher incidence of BrM, but a longer overall survival. The high response rate of both systemic and BrM EGFRact+ NSCLC to tyrosine kinase inhibitors (TKIs) has led to the rapid incorporation of new therapies but is outpacing evidence-based decisions for BrM in NSCLC. While whole brain radiation therapy (WBRT) was the foundation of management of BrM, extended survival raises concerns for the subacute and late effects radiotherapy. We favor the use of TKIs and delaying the use of WBRT when able. At inevitable disease progression, we consider alternative dosing schedules to increase CNS penetration (such as pulse dosing of erlotinib) or advance to next generation TKI if available. We utilize local control options of surgery or stereotactic radiosurgery (SRS) for symptomatic accessible lesions based on size and edema. At progression despite available TKIs, we use pemetrexed-based platinum doublet chemotherapy or immunotherapy if the tumor has high expression of PDL-1. We reserve the use of WBRT for patients with more than 10 BrM and progression despite TKI and conventional chemotherapy, if performance status is appropriate.

  View details for DOI 10.1007/s11864-017-0466-0

  View details for PubMedID 28391420

• Characterization of the peripheral neuropathy associated with brentuximab vedotin treatment of Mycosis Fungoides and Sézary Syndrome. Journal of neuro-oncology Corbin, Z. A., Nguyen-Lin, A., Li, S., Rahbar, Z., Tavallaee, M., Vogel, H., Salva, K. A., Wood, G. S., Kim, Y. H., Nagpal, S. 2017

  Abstract

  Chemotherapy-induced peripheral neuropathy (CIPN) is common, frequently limits chemotherapy dosing, and negatively impacts quality of life. The National Cancer Institute Common Toxicity Criteria for Adverse Events (CTCAE), version 4.0, and the Total Neuropathy Score clinical version (TNSc) are both validated scores to quantify peripheral neuropathy (PN), with the TNSc being more sensitive to clinical changes. Mycosis fungoides and Sézary syndrome (MF/SS) are characterized by a chronic course, where current therapies are generally non-curative and treatment toxicities have the potential for significant lasting effects. Brentuximab vedotin (BV) is an antibody-drug-conjugate composed of an anti-CD30 monoclonal antibody linked to the microtubule-disrupting agent, monomethyl auristatin E, with a known associated CIPN. In our phase II clinical trial of BV in MF/SS, 25 (69%) of 36 patients developed PN, with 18 (50%) developing Clinically Significant PN, CTCAE v4.0 grade 2 or higher. The median time to grade 2 PN was 15 weeks (range 0.4-48) after the initial dose. By Kaplan-Meier calculation, the median time to improvement from Clinically Significant PN was 30 weeks from the last BV dose. Seventy-four percent had improvement by 24 months. We found that TNSc scores significantly correlated with CTCAE grade, with Spearman correlation coefficient 0.68 (p < 0.001). By logistic regression, for each 100 mg increase in BV total dose, the likelihood of developing Clinically Significant PN increased by 23% (95% CI 4-46%). Improved monitoring of CIPN associated with BV is of paramount importance in the MF/SS population.

  View details for DOI 10.1007/s11060-017-2389-9

  View details for PubMedID 28271282

• Stereotactic Radiosurgery and Hypofractionated Radiotherapy for Glioblastoma. Neurosurgery Shah, J. L., Li, G., Shaffer, J. L., Azoulay, M. I., Gibbs, I. C., Nagpal, S., Soltys, S. G. 2017

  Abstract

  Glioblastoma is the most common primary brain tumor in adults. Standard therapy depends on patient age and performance status but principally involves surgical resection followed by a 6-wk course of radiation therapy given concurrently with temozolomide chemotherapy. Despite such treatment, prognosis remains poor, with a median survival of 16 mo. Challenges in achieving local control, maintaining quality of life, and limiting toxicity plague treatment strategies for this disease. Radiotherapy dose intensification through hypofractionation and stereotactic radiosurgery is a promising strategy that has been explored to meet these challenges. We review the use of hypofractionated radiotherapy and stereotactic radiosurgery for patients with newly diagnosed and recurrent glioblastoma.

  View details for PubMedID 28605463

• Optimizing bevacizumab dosing in glioblastoma: less is more. Journal of neuro-oncology Ajlan, A., Thomas, P., Albakr, A., Nagpal, S., Recht, L. 2017; 135 (1): 99–105

  Abstract

  Compared to traditional chemotherapies, where dose limiting toxicities represent the maximum possible dose, monoclonal antibody therapies are used at doses well below maximum tolerated dose. However, there has been little effort to ascertain whether there is a submaximal dose at which the efficacy/complication ratio is maximized. Thus, despite the general practice of using Bevacizumab (BEV) at dosages of 10 mg/kg every other week for glioma patients, there has not been much prior work examining whether the relatively high complication rates reported with this agent can be decreased by lowering the dose without impairing efficacy. We assessed charts from 80 patients who received BEV for glioblastoma to survey the incidence of complications relative to BEV dose. All patients were treated with standard upfront chemoradiation. The toxicity was graded based on the NCI CTCAE, version 4.03. The rate of BEV serious related adverse events was 12.5% (n = 10/80). There were no serious adverse events (≥grade 3) when the administered dose was (<3 mg/kg/week), compared to a 21% incidence in those who received higher doses (≥3 mg/kg/week) (P < 0.01). Importantly, the three patient deaths attributable to BEV administration occurred in patients receiving higher doses. Patients who received lower doses also had a better survival rate, although this did not reach statistical significance [median OS 39 for low dose group vs. 17.3 for high dose group (P = 0.07)]. Lower rates of serious BEV related toxicities are noted when lower dosages are used without diminishing positive clinical impact. Further work aimed at optimizing BEV dosage is justified.

  View details for PubMedID 28667595

• AN OVERVIEW OF DNA TOPOISOMERASE I INHIBITORS UNDER DEVELOPMENT DRUGS OF THE FUTURE Connolly, I. D., Hixson, J. D., Nagpal, S. 2016; 41 (12): 731-740

  View details for DOI 10.1358/dof.2016.041.12.2563475

  View details for Web of Science ID 000395939300003

• PS01.04: A Phase II Study of Etirinotecan Pegol (NKTR-102) in Patients with Refractory Brain Metastases and Advanced Lung Cancer: Topic: Medical Oncology. Journal of thoracic oncology Neal, J. W., Wakelee, H., Padda, S. K., Bertrand, S., Acevedo, B., Holmes Tisch, A., Pagtama, J. Y., Soltys, S. G., Nagpal, S. 2016; 11 (11S): S271-S272

  View details for DOI 10.1016/j.jtho.2016.09.040

  View details for PubMedID 27969472

• A Phase I/II Trial of 5 Fraction Stereotactic Radiosurgery With 5-mm Margins With Concurrent and Adjuvant Temozolomide in Newly Diagnosed Supratentorial Glioblastoma Multiforme. International journal of radiation oncology, biology, physics Azoulay, M., Ho, C. K., Fujimoto, D. K., Modlin, L. A., Gibbs, I. C., Hancock, S. L., Li, G., Chang, S. D., Adler, J. R., Harsh, G. R., Nagpal, S., Thomas, R., Recht, L., Choi, C. Y., Soltys, S. G. 2016; 96 (2S): E131-E132

  View details for DOI 10.1016/j.ijrobp.2016.06.921

  View details for PubMedID 27673859

• Tumor DNA in cerebral spinal fluid reflects clinical course in a patient with melanoma leptomeningeal brain metastases JOURNAL OF NEURO-ONCOLOGY Li, Y., Pan, W., Connolly, I. D., Reddy, S., Nagpal, S., Quake, S., Gephart, M. H. 2016; 128 (1): 93-100

  Abstract

  Cerebral spinal fluid (CSF) from brain tumor patients contains tumor cellular and cell-free DNA (cfDNA), which provides a less-invasive and routinely accessible method to obtain tumor genomic information. In this report, we used droplet digital PCR to test mutant tumor DNA in CSF of a patient to monitor the treatment response of metastatic melanoma leptomeningeal disease (LMD). The primary melanoma was known to have a BRAF (V600E) mutation, and the patient was treated with whole brain radiotherapy and BRAF inhibitors. We collected 9 CSF samples over 6 months. The mutant cfDNA fraction gradually decreased from 53 % (time of diagnosis) to 0 (time of symptom alleviation) over the first 6 time points. Three months after clinical improvement, the patient returned with severe symptoms and the mutant cfDNA was again detected in CSF at high levels. The mutant DNA fraction corresponded well with the patient's clinical response. We used whole exome sequencing to examine the mutation profiles of the LMD tumor DNA in CSF before therapeutic response and after disease relapse, and discovered a canonical cancer mutation PTEN (R130*) at both time points. The cellular and cfDNA revealed similar mutation profiles, suggesting cfDNA is representative of LMD cells. This study demonstrates the potential of using cellular or cfDNA in CSF to monitor treatment response for LMD.

  View details for DOI 10.1007/s11060-016-2081-5

  View details for PubMedID 26961773

• The "Liquid Biopsy": the Role of Circulating DNA and RNA in Central Nervous System Tumors. Current neurology and neuroscience reports Connolly, I. D., Li, Y., Gephart, M. H., Nagpal, S. 2016; 16 (3): 25-?

  Abstract

  The detection of tumor-derived circulating nucleic acids in patients with cancer, known as the "liquid biopsy," has expanded from use in plasma to other bodily fluids in an increasing number of malignancies. Circulating nucleic acids could be of particular use in central nervous system tumors as biopsy carries a 5-7 % risk of major morbidity. This application presents unique challenges that have limited the use of cell-free DNA and RNA in the diagnosis and monitoring of CNS tumors. Recent work suggests that cerebrospinal fluid may be a useful source of CNS tumor-derived circulating nucleic acids. In this review, we discuss the available data and future outlook on the use of the liquid biopsy for CNS tumors.

  View details for DOI 10.1007/s11910-016-0629-6

  View details for PubMedID 26838352

• Phase II Investigator-Initiated Study of Brentuximab Vedotin in Mycosis Fungoides and Sézary Syndrome With Variable CD30 Expression Level: A Multi-Institution Collaborative Project. Journal of clinical oncology Kim, Y. H., Tavallaee, M., Sundram, U., Salva, K. A., Wood, G. S., Li, S., Rozati, S., Nagpal, S., Krathen, M., Reddy, S., Hoppe, R. T., Nguyen-Lin, A., Weng, W., Armstrong, R., Pulitzer, M., Advani, R. H., Horwitz, S. M. 2015; 33 (32): 3750-3758

  Abstract

  In contrast to Hodgkin lymphoma and systemic anaplastic large-cell lymphoma, CD30 expression of malignant lymphocytes in mycosis fungoides (MF) and Sézary syndrome (SS) is quite variable. Clinical activity and safety of brentuximab vedotin, a CD30 targeting antibody-drug conjugate, was evaluated in MF and SS. Tissue and blood biomarkers of clinical response were explored.In this phase II study, patients with MF or SS with negligible to 100% CD30 expression levels were treated with brentuximab vedotin (1.8 mg/kg) every 3 weeks for a maximum of sixteen doses. The primary end point was overall global response rate. Secondary end points included correlation of tissue CD30 expression level with clinical response, time to response, duration of response, progression-free and event-free survivals, and safety.Of the 32 patients enrolled and treated, 30 patients had available efficacy evaluations. Objective global response was observed in 21 (70%) of 30 patients (90% CI, 53% to 83%). CD30 expression assessed by immunohistochemistry was highly variable, with a median CD30max of 13% (range, 0% to 100%). Those with <5% CD30 expression had a lower likelihood of global response than did those with 5% or greater CD30 expression (P < .005). CD163 positive tumor-associated macrophages, many of which coexpress CD30, were abundant in tissue. Peripheral neuropathy was the most common adverse event.Brentuximab vedotin demonstrated significant clinical activity in treatment-refractory or advanced MF or SS with a wide range of CD30 expression levels. Additional biomarker studies may help optimize rational design of combination therapies with brentuximab vedotin.

  View details for DOI 10.1200/JCO.2014.60.3969

  View details for PubMedID 26195720

• Glioblastoma Multiforme Recurrence: An Exploratory Study of F-18 FPPRGD(2) PET/CT1 RADIOLOGY Iagaru, A., Mosci, C., Mittra, E., Zaharchuk, G., Fischbein, N., Harsh, G., Li, G., Nagpal, S., Recht, L., Gambhir, S. S. 2015; 277 (2): 497-506

  Abstract

  Purpose To prospectively evaluate fluorine 18 ((18)F) 2-fluoropropionyl-labeled PEGylated dimeric arginine-glycine-aspartic acid (RGD) peptide (PEG3-E[c{RGDyk}]2) (FPPRGD2) positron emission tomography (PET) in patients with glioblastoma multiforme (GBM). Materials and Methods The institutional review board approved this HIPAA-compliant protocol. Written informed consent was obtained from each patient. (18)F FPPRGD2 uptake was measured semiquantitatively in the form of maximum standardized uptake values (SUVmax) and uptake volumes before and after treatment with bevacizumab. Vital signs and laboratory results were collected before, during, and after the examinations. A nonparametric version of multivariate analysis of variance was used to assess safety outcome measures simultaneously across time points. A paired two-sample t test was performed to compare SUVmax. Results A total of 17 participants (eight men, nine women; age range, 25-65 years) were enrolled prospectively. (18)F FPPRGD2 PET/computed tomography (CT), (18)F fluorodeoxyglucose (FDG) PET/CT, and brain magnetic resonance (MR) imaging were performed within 3 weeks, prior to the start of bevacizumab therapy. In eight of the 17 patients (47%), (18)F FPPRGD2 PET/CT was repeated 1 week after the start of bevacizumab therapy; six patients (35%) underwent (18)F FPPRGD2 PET/CT a third time 6 weeks after starting bevacizumab therapy. There were no changes in vital signs, electrocardiographic findings, or laboratory values that qualified as adverse events. One patient (6%) had recurrent GBM identified only on (18)F FPPRGD2 PET images, and subsequent MR images enabled confirmation of recurrence. Of the 17 patients, 14 (82%) had recurrent GBM identified on (18)F FPPRGD2 PET and brain MR images, while (18)F FDG PET enabled identification of recurrence in 13 (76%) patients. Two patients (12%) had no recurrent GBM. Conclusion (18)F FPPRGD2 is a safe PET radiopharmaceutical that has increased uptake in GBM lesions. Larger cohorts are required to confirm these preliminary findings. (©) RSNA, 2015 Online supplemental material is available for this article.

  View details for DOI 10.1148/radiol.2015141550

  View details for Web of Science ID 000368435100026

• Phase II pilot study of single-agent etirinotecan pegol (NKTR-102) in bevacizumab-resistant high grade glioma JOURNAL OF NEURO-ONCOLOGY Nagpal, S., Recht, C. K., Bertrand, S., Thomas, R. P., Ajlan, A., Pena, J., Gershon, M., Coffey, G., Kunz, P. L., Li, G., Recht, L. D. 2015; 123 (2): 277-282

  Abstract

  Patients with recurrence of high-grade glioma (HGG) after bevacizumab (BEV) have an extremely poor prognosis. Etirinotecan pegol (EP) is the first long-acting topoisomerase-I inhibitor designed to concentrate in and provide continuous tumor exposure throughout the entire chemotherapy cycle. Here we report results of a Phase 2, single arm, open-label trial evaluating EP in HGG patients who progressed after BEV. Patients age >18 with histologically proven anaplastic astrocytoma or glioblastoma (GB) who previously received standard chemo-radiation and recurred after BEV were eligible. A predicted life expectancy >6 weeks and KPS ≥ 50 were required. The primary endpoint was PFS at 6-weeks. Secondary endpoint was overall survival from first EP infusion. Response was assessed by RANO criteria. Single agent EP was administered IV every 3 weeks at 145 mg/m2. Patients did not receive BEV while on EP. 20 patients (90 % GB) were enrolled with a median age of 50 and median KPS of 70. Three patients with GB (16.7 % of GB) had partial MRI responses. 6-week PFS was 55 %. Median and 6-month PFS were 2.2 months (95 % CI 1.4-3.4 months) and 11.2 % (95 % CI 1.9-28.9 %) respectively. Median overall survival from first EP infusion was 4.5 months (95 % CI 2.4-5.9). Only one patient had grade 3 toxicity (diarrhea with dehydration) attributable to EP. Hematologic toxicity was mild. Three patients had confirmed partial responses according to RANO criteria. These clinical data combined with a favorable safety profile warrant further clinical investigation of this agent in HGG.

  View details for DOI 10.1007/s11060-015-1795-0

  View details for PubMedID 25935109

• Cerebral Blood Flow Changes in Glioblastoma Patients Undergoing Bevacizumab Treatment Are Seen in Both Tumor and Normal Brain. The neuroradiology journal Andre, J. B., Nagpal, S., Hippe, D. S., Ravanpay, A. C., Schmiedeskamp, H., Bammer, R., Palagallo, G. J., Recht, L., Zaharchuk, G. 2015; 28 (2): 112-119

  Abstract

  Bevacizumab (BEV) is increasingly used to treat recurrent glioblastoma (GBM) with some reported improvement in neurocognitive function despite potential neurotoxicities. We examined the effects of BEV on cerebral blood flow (CBF) within recurrent GBM tumor and in the contralateral middle cerebral artery (MCA) territory.Post-chemoradiation patients with histologically confirmed GBM were treated with BEV and underwent routine, serial tumor imaging with additional pseudocontinuous arterial spin labeling (pcASL) following informed consent. Circular regions-of-interest were placed on pcASL images directly over the recurrent tumor and in the contralateral MCA territory. CBF changes before and during BEV treatment were evaluated in tumor and normal tissue. Linear mixed models were used to assess statistical significance.Fifty-three pcASL studies in 18 patients were acquired. Evaluation yielded lower mean tumoral CBF during BEV treatment compared with pre-treatment (45 ± 27 vs. 65 ± 27 ml/100 g/min, p = 0.002), and in the contralateral MCA territory during, compared with pre-BEV treatment (35 ± 8.4 vs. 41 ± 8.4 ml/100 g/min, p = 0.03). The decrease in mean CBF tended to be greater in the tumoral region than in the contralateral MCA, though the difference did not reach statistical significance (31% vs. 13%; p = 0.082).BEV administration results in statistically significant global CBF decrease with a potentially preferential decrease in tumor perfusion compared with normal brain tissue.

  View details for DOI 10.1177/1971400915576641

  View details for PubMedID 25923677

• Brain Tumor Mutations Detected in Cerebral Spinal Fluid CLINICAL CHEMISTRY Pan, W., Gu, W., Nagpal, S., Gephart, M. H., Quake, S. R. 2015; 61 (3): 514-522

  Abstract

  Detecting tumor-derived cell-free DNA (cfDNA) in the blood of brain tumor patients is challenging, presumably owing to the blood-brain barrier. Cerebral spinal fluid (CSF) may serve as an alternative "liquid biopsy" of brain tumors by enabling measurement of circulating DNA within CSF to characterize tumor-specific mutations. Many aspects about the characteristics and detectability of tumor mutations in CSF remain undetermined.We used digital PCR and targeted amplicon sequencing to quantify tumor mutations in the cfDNA of CSF and plasma collected from 7 patients with solid brain tumors. Also, we applied cancer panel sequencing to globally characterize the somatic mutation profile from the CSF of 1 patient with suspected leptomeningeal disease.We detected tumor mutations in CSF samples from 6 of 7 patients with solid brain tumors. The concentration of the tumor mutant alleles varied widely between patients, from <5 to nearly 3000 copies/mL CSF. We identified 7 somatic mutations from the CSF of a patient with leptomeningeal disease by use of cancer panel sequencing, and the result was concordant with genetic testing on the primary tumor biopsy.Tumor mutations were detectable in cfDNA from the CSF of patients with different primary and metastatic brain tumors. We designed 2 strategies to characterize tumor mutations in CSF for potential clinical diagnosis: the targeted detection of known driver mutations to monitor brain metastasis and the global characterization of genomic aberrations to direct personalized cancer care.

  View details for DOI 10.1373/clinchem.2014.235457

  View details for Web of Science ID 000352161300013

  View details for PubMedID 25605683

• Prolonged survival of patients with non-small-cell lung cancer with leptomeningeal carcinomatosis in the modern treatment era. Clinical lung cancer Riess, J. W., Nagpal, S., Iv, M., Zeineh, M., Gubens, M. A., Ramchandran, K., Neal, J. W., Wakelee, H. A. 2014; 15 (3): 202-206

  Abstract

  Leptomeningeal carcinomatosis (LM) is a severe complication of non-small-cell lung cancer (NSCLC) historically associated with poor prognosis. New chemotherapeutic and targeted treatments could potentially affect the natural history of LM.Patients with a pathologic diagnosis of NSCLC with LM treated at Stanford between 2003 and 2011 were identified via institutional databases and medical records. LM was defined by cerebrospinal fluid (CSF) that was positive for malignant cells or by LM enhancement on magnetic resonance imaging with gadolinium contrast. Retrospective, landmark analyses were performed to estimate survival. Statistical analyses were performed using SAS Enterprise Guide, version 4.3.LM was identified in 30 patients. All cases were adenocarcinoma; 60% of patients had a known or suspected driver mutation. The mean age was 58 years. Of the 30 patients, 67% were women; 70% were nonsmokers; 27% initially presented with LM; 84% received systemic treatment at or after development of LM; and 53% of these patients received modern systemic therapy for their LM, defined as a regimen containing pemetrexed, bevacizumab, or a tyrosine kinase inhibitor. Mean overall survival after LM diagnosis was 6 months (95% CI, 3-12). Patients who received modern systemic therapy for LM had decreased hazard of death (hazard ratio [HR], 0.24; P = .007).In this retrospective, single-institution analysis, median survival with LM was higher compared with historical experience. Patients who received modern systemic therapy for their LM had particularly good outcomes. These data provide evidence for improving survival outcomes in the modern treatment era for this difficult-to-treat complication.

  View details for DOI 10.1016/j.cllc.2013.12.009

  View details for PubMedID 24524822

• Risk of Leptomeningeal Disease in Patients Treated With Stereotactic Radiosurgery Targeting the Postoperative Resection Cavity for Brain Metastases INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Atalar, B., Modlin, L. A., Choi, C. Y., Adler, J. R., Gibbs, I. C., Chang, S. D., Harsh, G. R., Li, G., Nagpal, S., Hanlon, A., Soltys, S. G. 2013; 87 (4): 713-718

  Abstract

  We sought to determine the risk of leptomeningeal disease (LMD) in patients treated with stereotactic radiosurgery (SRS) targeting the postsurgical resection cavity of a brain metastasis, deferring whole-brain radiation therapy (WBRT) in all patients.We retrospectively reviewed 175 brain metastasis resection cavities in 165 patients treated from 1998 to 2011 with postoperative SRS. The cumulative incidence rates, with death as a competing risk, of LMD, local failure (LF), and distant brain parenchymal failure (DF) were estimated. Variables associated with LMD were evaluated, including LF, DF, posterior fossa location, resection type (en-bloc vs piecemeal or unknown), and histology (lung, colon, breast, melanoma, gynecologic, other).With a median follow-up of 12 months (range, 1-157 months), median overall survival was 17 months. Twenty-one of 165 patients (13%) developed LMD at a median of 5 months (range, 2-33 months) following SRS. The 1-year cumulative incidence rates, with death as a competing risk, were 10% (95% confidence interval [CI], 6%-15%) for developing LF, 54% (95% CI, 46%-61%) for DF, and 11% (95% CI, 7%-17%) for LMD. On univariate analysis, only breast cancer histology (hazard ratio, 2.96) was associated with an increased risk of LMD. The 1-year cumulative incidence of LMD was 24% (95% CI, 9%-41%) for breast cancer compared to 9% (95% CI, 5%-14%) for non-breast histology (P=.004).In patients treated with SRS targeting the postoperative cavity following resection, those with breast cancer histology were at higher risk of LMD. It is unknown whether the inclusion of whole-brain irradiation or novel strategies such as preresection SRS would improve this risk or if the rate of LMD is inherently higher with breast histology.

  View details for DOI 10.1016/j.ijrobp.2013.07.034

  View details for Web of Science ID 000325763300022

  View details for PubMedID 24054875

• Simultaneous perfusion and permeability measurements using combined spin- and gradient-echo MRI. Journal of cerebral blood flow and metabolism Schmiedeskamp, H., Andre, J. B., Straka, M., Christen, T., Nagpal, S., Recht, L., Thomas, R. P., Zaharchuk, G., Bammer, R. 2013; 33 (5): 732-743

  Abstract

  The purpose of this study was to estimate magnetic resonance imaging-based brain perfusion parameters from combined multiecho spin-echo and gradient-echo acquisitions, to correct them for T1-, T2-, and -related contrast agent (CA) extravasation effects, and to simultaneously determine vascular permeability. Perfusion data were acquired using a combined multiecho spin- and gradient-echo (SAGE) echo-planar imaging sequence, which was corrected for CA extravasation effects using pharmacokinetic modeling. The presented method was validated in simulations and brain tumor patients, and compared with uncorrected single-echo and multiecho data. In the presence of CA extravasation, uncorrected single-echo data resulted in underestimated CA concentrations, leading to underestimated single-echo cerebral blood volume (CBV) and mean transit time (MTT). In contrast, uncorrected multiecho data resulted in overestimations of CA concentrations, CBV, and MTT. The correction of CA extravasation effects resulted in CBV and MTT estimates that were more consistent with the underlying tissue characteristics. Spin-echo perfusion data showed reduced large-vessel blooming effects, facilitating better distinction between increased CBV due to active tumor progression and elevated CBV due to the presence of cortical vessels in tumor proximity. Furthermore, extracted permeability parameters were in good agreement with elevated T1-weighted postcontrast signal values.

  View details for DOI 10.1038/jcbfm.2013.10

  View details for PubMedID 23462570

• A Patient With Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer With Development of Leptomeningeal Carcinomatosis While on Targeted Treatment With Crizotinib JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Riess, J. W., Nagpal, S., Neal, J. W., Wake, H. A. 2013; 11 (4): 389-394

  Abstract

  Leptomeningeal carcinomatosis (LM) is an infrequent yet morbid and often fatal complication of non-small cell lung cancer (NSCLC). Management of LM is multimodal, often involving systemic chemotherapy, radiotherapy, and a variety of symptom management maneuvers to address elevated intracranial pressure, pain, and mood changes that can accompany the disease. It is increasingly recognized that tumors with actionable mutations in NSCLC, including epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) translocations, respond well to systemic therapy with tyrosine kinase inhibitors yet often progress in the central nervous system. More information is needed regarding the natural history and optimal management of LM in specific molecular subtypes of NSCLC. This case report summarizes the management of a patient with ALK-positive NSCLC who developed LM while on targeted treatment with crizotinib within the context of current NCCN Clinical Practice Guidelines in Oncology and recently published studies.

  View details for PubMedID 23584342

• ETIRINOTECAN PEGOL DNA Topoisomerase 1 Inhibitor Oncolytic DRUGS OF THE FUTURE Nagpal, S., Recht, L. D. 2013; 38 (4): 227-233

  View details for DOI 10.1358/dof.2013.38.4.1939287

  View details for Web of Science ID 000317927900003

• The incidence and significance of multiple lesions in glioblastoma JOURNAL OF NEURO-ONCOLOGY Thomas, R. P., Xu, L. W., Lober, R. M., Li, G., Nagpal, S. 2013; 112 (1): 91-97

  Abstract

  The location and distribution of glioblastoma (GBM) within the brain parenchyma plays an important role in surgical and radiation planning. Prior studies have reported incidences of multiple lesions at the time of diagnosis ranging from 0.5 to 20 %. Multiple lesions can be further categorized as multifocal (multiple areas involved, but with a clear path of spread from one lesion to another) or multicentric (multiple lesions, no clear path of spread). In this retrospective study, we reviewed our experience with GBM and found the incidence of multiple lesions at time of diagnosis was 35 %, much higher than previously suggested in the literature. Patients with single lesions had an improved overall survival when compared to patients with multiple lesions (18 vs. 10 months). Patients with multicentric lesions fared the worst, with average survival of 3 months. However, the difference between single and multiple lesions (multifocal or multicentric) was no longer significant when taking into consideration age, Karnofsky performance score (KPS) and extent of resection by multivariate analysis. Age, KPS, gross total resection, and MGMT status were independent predictors of outcome. Multiple lesions did not independently confer a worse outcome, but were associated with lower KPS scores and inability to perform gross total resection. These findings suggest that single, multiple and multicentric imaging exams represent a spectrum of presentations of a single disease. The rate of multiple lesions reported here may be the result of improved imaging technology, suggesting that incidence of multiple lesions will continue to increase as imaging technology advances.

  View details for DOI 10.1007/s11060-012-1030-1

  View details for PubMedID 23354652

• A case series of NSCLC patients with different molecular characteristics and choroidal metastases: improvement in vision with treatment including pemetrexed and bevacizumab. Journal of thoracic oncology Riess, J. W., Nagpal, S., Das, M., Neal, J. W., Kim, J. W., Wakelee, H. A. 2013; 8 (2): e17-8

  View details for DOI 10.1097/JTO.0b013e31827690da

  View details for PubMedID 23328555

  View details for PubMedCentralID PMC3552378

• EGFR mutation status and brain metastases in non-small cell lung cancer: an understudied problem TRANSLATIONAL CANCER RESEARCH Riess, J. W., Nagpal, S. 2013; 2 (1): 54-56

  View details for DOI 10.3978/j.issn.2218-676X.2013.02.06

  View details for Web of Science ID 000209642900010

• A Case Series of NSCLC Patients with Different Molecular Characteristics and Choroidal Metastases Improvement in Vision with Treatment Including Pemetrexed and Bevacizumab JOURNAL OF THORACIC ONCOLOGY Riess, J. W., Nagpal, S., Das, M., Neal, J. W., Kim, J. W., Wakelee, H. A. 2013; 8 (2): E17-E18

  View details for DOI 10.1097/JTO.0b013e31827690da

  View details for Web of Science ID 000316204900003

  View details for PubMedID 23328555

  View details for PubMedCentralID PMC3552378

• Advances in the management of glioblastoma: the role of temozolomide and MGMT testing. Clinical pharmacology : advances and applications Thomas, R. P., Recht, L., Nagpal, S. 2013; 5: 1-9

  Abstract

  Glioblastoma (GB) is one of the most lethal forms of cancer, with an invasive growth pattern that requires the use of adjuvant therapies, including chemotherapy and radiation, to prolong survival. Temozolomide (TMZ) is an oral chemotherapy with a limited side effect profile that has become the standard of care in GB treatment. While TMZ has made an impact on survival, tumor recurrence and TMZ resistance remain major challenges. Molecular markers, such as O6-methylguanine-DNA methyltransferase methylation status, can be helpful in predicting tumor response to TMZ, and therefore guides clinical decision making. This review will discuss the epidemiology and possible genetic underpinnings of GB, how TMZ became the standard of care for GB patients, the pharmacology of TMZ, the practical aspects of using TMZ in clinic, and how molecular diagnostics - particularly the use of O6-methylguanine-DNA methyltransferase status - affect clinical management.

  View details for DOI 10.2147/CPAA.S26586

  View details for PubMedID 23293540

• Treatment of Leptomeningeal Spread of NSCLC: A Continuing Challenge CURRENT TREATMENT OPTIONS IN ONCOLOGY Nagpal, S., Riess, J., Wakelee, H. 2012; 13 (4): 491-504

  Abstract

  OPINION STATEMENT: Leptomeningeal metastasis is a serious and frequently fatal complication of non-small cell lung cancer. Curative treatment remains elusive, but careful use of radiation, systemic chemotherapy, intrathecal chemotherapy, and symptoms management can greatly improve quality of life and survival. For most patients, we recommend a combination of skull-based radiation with focal radiation to any symptomatic spinal segments followed by systemic chemotherapy. For patients with EGFR mutations, erlotinib may be used as first-line therapy in a daily or high-dose regimen. Pemetrexed has promise for use in patients with brain and leptomeningeal metastases. Patients with multiple comorbidities or low performance status may tolerate intrathecal therapy better than systemic chemotherapy. The most commonly used intrathecal chemotherapies are methotrexate and liposomal cytarabine, although newer agents, such as topotecan and mafosfamide, may be more effective. Elevated intracranial pressure, which causes headaches, vertigo, nausea, and vomiting, should be treated with dexamethasone and acetazolamide. In select patients, cerebrospinal fluid shunting may be considered. The use of antidepressants, central nervous system stimulants, benzodiazepines, antiemetics, and pain medications can increase quality of life in patients with leptomeningeal metastases.

  View details for DOI 10.1007/s11864-012-0206-4

  View details for Web of Science ID 000311292500006

  View details for PubMedID 22836285

• Polymer Wafers (Gliadel) in the Treatment of Malignant Glioma NEUROSURGERY CLINICS OF NORTH AMERICA Nagpal, S. 2012; 23 (2): 289-?

  Abstract

  The 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU; carmustine) polymer wafer (Gliadel) was developed for use in malignant glioma to deliver higher doses of chemotherapy directly to tumor tissue while bypassing systemic side effects. Phase III clinical trials for patients with newly diagnosed malignant gliomas demonstrated a small, but statistically significant, improvement in survival. However, the rate of complications, including an increase in cerebrospinal fluid leaks and intracranial hypertension, has limited their use. This article reviews the current data for use of BCNU wafers in malignant gliomas.

  View details for DOI 10.1016/j.nec.2012.01.004

  View details for Web of Science ID 000303282100011

  View details for PubMedID 22440872

• Neoplastic Myelopathy SEMINARS IN NEUROLOGY Nagpal, S., Clarke, J. L. 2012; 32 (2): 137-145

  Abstract

  Neoplastic myelopathy may be due to external compression or to direct intraparenchymal involvement of the spinal cord. In this review, the authors discuss the most common cause for compressive neoplastic myelopathy, metastatic disease. They also review other compressive lesions and discuss primary intramedullary spinal tumors. In the acute setting, compressive metastatic disease should be treated with high-dose steroids when clinically necessary; surgery should be considered for selected patients, followed by radiation therapy. For most primary intramedullary spinal tumors, surgical resection remains the standard initial therapy. Patients with incomplete resection of infiltrative tumors, high-grade pathology, or recurrent tumors may benefit from radiation, but most spinal tumors are relatively insensitive to traditional chemotherapy. Neoplastic myelopathy from either compressive or intraparenchymal causes remains a diagnostic and therapeutic challenge. In complex cases, referral to a specialty center with access to neurosurgeons, neuroradiologists, neuropathologists, and neurooncologists is recommended.

  View details for DOI 10.1055/s-0032-1322584

  View details for Web of Science ID 000307423200005

  View details for PubMedID 22961188

• Treatment and Prophylaxis of Hematologic Malignancy in the Central Nervous System CURRENT TREATMENT OPTIONS IN NEUROLOGY Nagpal, S., Recht, L. 2011; 13 (4): 400-412

  Abstract

  OPINION STATEMENT: Central nervous system (CNS) involvement is a serious, and frequently fatal, complication of acute leukemias and very aggressive lymphomas. In patients with no evidence of CNS involvement at the time of diagnosis, the decision to include CNS prophylaxis in the treatment regimen should be based on cytologic diagnosis and other risk factors. Patients with a risk of CNS relapse greater than 10% should receive CNS prophylaxis with high-dose systemic chemotherapy, intrathecal therapy, radiation, or a combination thereof. The most commonly used systemic and intrathecal chemotherapies are methotrexate and cytarabine. Liposomal cytarabine, which increases CNS bioavailability and decreases the number of lumbar punctures needed, is our preference for intrathecal therapy. We usually reserve radiation therapy for patients who may not tolerate other forms of CNS prophylaxis. Patients with evidence of CNS involvement, either at diagnosis or relapse, should be treated until CNS disease clearance or dose-limiting toxicity is reached. Recent studies suggest that autologous stem cell transplantation may offer longer survivals for patients with CNS involvement and should be considered for patients who can tolerate the procedure. The use of rituximab in CNS prophylaxis and treatment has not yet been clearly delineated, but initial reports indicate that this agent and others may soon be available as an effective and tolerable CNS-directed therapy for lymphomas.

  View details for DOI 10.1007/s11940-011-0128-7

  View details for Web of Science ID 000292402500007

  View details for PubMedID 21484261

• Bevacizumab improves quality of life in patients with recurrent glioblastoma. Chemotherapy research and practice Nagpal, S., Harsh, G., Recht, L. 2011; 2011: 602812-?

  Abstract

  Objective. To quantify the benefits in survival and quality of life in patients receiving bevacizumab (BEV) for recurrent glioblastoma (GBM). Methods. This is a retrospective study of 40 adult patients with recurrent GBM treated between 2005 and 2009 at a single institution. All patients had initial treatment with surgery, radiation, and concurrent temozolomide, then monthly temozolomide. Over 250 charts were screened. Sufficient data was available for 20 patients treated with BEV and 20 patients who did not receive BEV at the time of recurrence. The independent living score (ILS), designed to reward long-term independent survival, was calculated for each patient. Results. The mean ILS was nearly double in the BEV group compared to the No-BEV group (15.0 versus 8.2, P = 0.002, t-test). Two months after initiation of therapy, the median steroid dose dropped by over 90% in patients treated with BEV, but doubled in the NoBEV group. Median survival from the time of recurrence was significantly affected: 10.6 months in the BEV group versus 4.2 months (P < 0.001, log rank survival) in the NoBEV group. Conclusions. BEV increases independent living and lengthens overall survival after GBM recurrence. Reduction in steroid dose may contribute to prolonged independence.

  View details for DOI 10.1155/2011/602812

  View details for PubMedID 22312554

  View details for PubMedCentralID PMC3263615

• Cardiac Rupture After Intravenous t-PA Administration in Acute Ischemic Stroke NEUROCRITICAL CARE Dhand, A., Nakagawa, K., Nagpal, S., Gelfand, J. M., Kim, A. S., Smith, W. S., Tihan, T. 2010; 13 (2): 261-262

  Abstract

  Ventricular free wall rupture is a fatal complication of myocardial infarction (MI). Although described in MI patients who receive thrombolytic therapy, this complication is not well known in ischemic stroke patients who receive intravenous (IV) t-PA.Case report.We present a 93-year-old woman with an acute onset of a right middle cerebral artery syndrome in the setting of subacute MI. IV t-PA was administered and she subsequently developed asystolic arrest and died. Autopsy showed subacute MI, hemopericardium, and rupture of the left ventricle.This case illustrates a fatal cardiac complication of IV thrombolytic therapy for stroke. The speculated mechanism is hemorrhage into the infarcted myocardium.

  View details for DOI 10.1007/s12028-010-9384-8

  View details for Web of Science ID 000282093500018

  View details for PubMedID 20697837

• Treatment and Prevention of Secondary CNS Lymphoma SEMINARS IN NEUROLOGY Nagpal, S., Glantz, M. J., Recht, L. 2010; 30 (3): 263-272

  Abstract

  Central nervous system (CNS) involvement in non-Hodgkin lymphoma is a serious, potentially preventable complication that can occur in 5 to 10% of patients. Its occurrence is directly correlated with pathologic aggressiveness and ranges from less than 3% in the indolent, less-aggressive histologies to as high as 50% in the very aggressive ones such as Burkitt lymphoma. Aggressive treatment once detected can improve neurologic outcome, but because it is often associated with contemporaneous systemic relapse, is rarely associated with long-term survival. Preventing its occurrence, therefore, remains an important goal of initial treatment. Despite there being some suggestive evidence that the addition of systemic rituximab and several intracerebrospinal fluid chemotherapy regimens may have decreased the incidence of CNS involvement, both optimal selection of those patients who should receive prophylaxis as well as the best prophylactic regimen remain active areas of investigation.

  View details for DOI 10.1055/s-0030-1255222

  View details for Web of Science ID 000279572600007

  View details for PubMedID 20577933

• Decompressive laparotomy to treat intractable cerebral hypoxia. journal of trauma Nagpal, S., Halpern, C. H., Sims, C., Calland, J. F., Gracias, V. H., Schuster, J. M., LeRoux, P. D., Levine, J. M. 2009; 67 (5): E152-5

  View details for DOI 10.1097/TA.0b013e3180593657

  View details for PubMedID 19088554

• Vasospasm as the sole cause of cerebral ischemia: how strong is the evidence? Neurosurgical focus Stein, S. C., Levine, J. M., Nagpal, S., LeRoux, P. D. 2006; 21 (3): E2-?

  Abstract

  The authors review literature that challenges the view that vasospasm involving large arteries is the exclusive cause of delayed ischemic neurological deficits (DINDs) following subarachnoid hemorrhage. They discuss alternative mechanisms and review the evidence supporting a potential role for thromboembolism. They conclude that vasospasm and thromboembolism play interrelated and additive roles in the development of DINDs, and that this interaction provides opportunities for novel therapeutic approaches.

  View details for PubMedID 17029341

• Management of patients with Schwan nomatosis: Report of six cases and review of the literature SURGICAL NEUROLOGY Huang, J. H., Simon, S. L., Nagpal, S., Nelson, P. T., Zager, E. L. 2004; 62 (4): 353-361

  Abstract

  Schwannomatosis is a rare tumor syndrome characterized by the presence of multiple schwannomas without the stigmata of neurofibromatosis (NF) Type 1 or 2. To better understand the natural history and clinical management of the syndrome, a retrospective review was conducted of patients diagnosed with schwannomatosis over an 11-year period at the University of Pennsylvania Medical Center (UPMC).Between 1990 and 2001, 131 patients underwent surgery for resection of spinal or peripheral nerve schwannomas in the Department of Neurosurgery at the University of Pennsylvania Medical Center. Among the 131 patients, there were 6 who had two or more pathologically proven schwannomas without radiographic or clinical evidence of vestibular schwannomas. The hospital charts, clinic notes, radiology films, operative reports, pathology slides, and reports from all 6 patients were retrospectively reviewed.The patient population consisted of 6 patients with a mean age of 48.7 (3 male: 3 female). All patients had enhanced brain magnetic resonance imaging (MRI) scans that were negative for vestibular schwannomas. Ophthalmological and general physical examinations did not reveal any findings suggestive of NF. There was no family history of NF or schwannomatosis. The locations of the schwannomas included intraspinal (multiple sites), paraspinal, brachial plexus, femoral nerve, sciatic nerve, calf, forearm, retroperitoneum, and middle cranial/infratemporal fossa region. The common presenting symptoms included paresthesias, palpable mass, pain, or weakness. All 6 patients underwent surgical resection of symptomatic lesions.For patients with schwannomatosis, surgery is indicated for symptomatic lesions, while asymptomatic tumors are followed conservatively. Because these patients are at increased risk for developing multiple schwannomas, we recommend regular surveillance and offer genetic counseling even though the pattern of inheritance is unknown.

  View details for DOI 10.1016/j.surneu.2003.11.020

  View details for Web of Science ID 000224263300013

  View details for PubMedID 15451291