35 results on '"Wen, Patrick Y"'
Search Results
2. Re-irradiation of recurrent IDH-wildtype glioblastoma in the bevacizumab and immunotherapy era: Target delineation, outcomes and patterns of recurrence
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Christ, Sebastian M., Youssef, Gilbert, Tanguturi, Shyam K., Cagney, Daniel, Shi, Diana, McFaline-Figueroa, J. Ricardo, Chukwueke, Ugonma, Lee, Eudocia Q., Hertler, Caroline, Andratschke, Nicolaus, Weller, Michael, Reardon, David A., Haas-Kogan, Daphne, Guckenberger, Matthias, Wen, Patrick Y., and Rahman, Rifaquat
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- 2024
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3. Impact of pemetrexed on intracranial disease control and radiation necrosis in patients with brain metastases from non-small cell lung cancer receiving stereotactic radiation
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Cagney, Daniel N., Martin, Allison M., Catalano, Paul J., Reitman, Zachary J., Mezochow, Gabrielle A., Lee, Eudocia Q., Wen, Patrick Y., Weiss, Stephanie E., Brown, Paul D., Ahluwalia, Manmeet S., Arvold, Nils D., Tanguturi, Shyam K., Haas-Kogan, Daphne A., Alexander, Brian M., Redig, Amanda J., and Aizer, Ayal A.
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- 2018
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4. Tumor associated seizures in glioblastomas are influenced by survival gene expression in a region-specific manner: A gene expression imaging study
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Lee, Jong Woo, Norden, Andrew D., Ligon, Keith L., Golby, Alexandra J., Beroukhim, Rameen, Quackenbush, John, Wells, William, Oelschlager, Kristen, Maetzold, Derek, and Wen, Patrick Y.
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- 2014
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5. Dabrafenib plus trametinib in patients with BRAFV600E-mutant low-grade and high-grade glioma (ROAR): a multicentre, open-label, single-arm, phase 2, basket trial.
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Wen, Patrick Y, Stein, Alexander, van den Bent, Martin, De Greve, Jacques, Wick, Antje, de Vos, Filip Y F L, von Bubnoff, Nikolas, van Linde, Myra E, Lai, Albert, Prager, Gerald W, Campone, Mario, Fasolo, Angelica, Lopez-Martin, Jose A, Kim, Tae Min, Mason, Warren P, Hofheinz, Ralf-Dieter, Blay, Jean-Yves, Cho, Daniel C, Gazzah, Anas, and Pouessel, Damien
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GLIOMAS , *BRAIN tumors , *ASTROCYTOMAS , *GLIOBLASTOMA multiforme , *BRAF genes , *BASKETS - Abstract
Background: Effective treatments are needed to improve outcomes for high-grade glioma and low-grade glioma. The activity and safety of dabrafenib plus trametinib were evaluated in adult patients with recurrent or progressive BRAFV600E mutation-positive high-grade glioma and low-grade glioma.Methods: This study is part of an ongoing open-label, single-arm, phase 2 Rare Oncology Agnostic Research (ROAR) basket trial at 27 community and academic cancer centres in 13 countries (Austria, Belgium, Canada, France, Germany, Italy, Japan, the Netherlands, Norway, South Korea, Spain, Sweden, and the USA). The study enrolled patients aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0, 1, or 2. Patients with BRAFV600E mutation-positive high-grade glioma and low-grade glioma received dabrafenib 150 mg twice daily plus trametinib 2 mg once daily orally until unacceptable toxicity, disease progression, or death. In the high-grade glioma cohort, patients were required to have measurable disease at baseline using the Response Assessment in Neuro-Oncology high-grade glioma response criteria and have been treated previously with radiotherapy and first-line chemotherapy or concurrent chemoradiotherapy. Patients with low-grade glioma were required to have measurable non-enhancing disease (except pilocytic astrocytoma) at baseline using the Response Assessment in Neuro-Oncology low-grade glioma criteria. The primary endpoint, in the evaluable intention-to-treat population, was investigator-assessed objective response rate (complete response plus partial response for high-grade glioma and complete response plus partial response plus minor response for low-grade glioma). This trial is ongoing, but is closed for enrolment, NCT02034110.Findings: Between April 17, 2014, and July 25, 2018, 45 patients (31 with glioblastoma) were enrolled into the high-grade glioma cohort and 13 patients were enrolled into the low-grade glioma cohort. The results presented here are based on interim analysis 16 (data cutoff Sept 14, 2020). In the high-grade glioma cohort, median follow-up was 12·7 months (IQR 5·4-32·3) and 15 (33%; 95% CI 20-49) of 45 patients had an objective response by investigator assessment, including three complete responses and 12 partial responses. In the low-grade glioma cohort, median follow-up was 32·2 months (IQR 25·1-47·8). Nine (69%; 95% CI 39-91) of 13 patients had an objective response by investigator assessment, including one complete response, six partial responses, and two minor responses. Grade 3 or worse adverse events were reported in 31 (53%) patients, the most common being fatigue (five [9%]), decreased neutrophil count (five [9%]), headache (three [5%]), and neutropenia (three [5%]).Interpretation: Dabrafenib plus trametinib showed clinically meaningful activity in patients with BRAFV600E mutation-positive recurrent or refractory high-grade glioma and low-grade glioma, with a safety profile consistent with that in other indications. BRAFV600E testing could potentially be adopted in clinical practice for patients with glioma.Funding: Novartis. [ABSTRACT FROM AUTHOR]- Published
- 2022
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6. IDH-mutant gliomas with additional class-defining molecular events.
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Ahrendsen, Jared T., Torre, Matthew, Meredith, David M., Hornick, Jason L., Reardon, David A., Wen, Patrick Y., Yeo, Kee K., Malinowski, Seth, Ligon, Keith L., Ramkissoon, Shakti, and Alexandrescu, Sanda
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- 2021
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7. Pneumocystis carinii pneumonia during steroid taper in patients with primary brain tumors
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Slivka, Adam, Wen, Patrick Y., Shea, W. Michael, and Loeffler, Jay S.
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Corticosteroids -- Adverse and side effects ,Brain tumors -- Care and treatment ,Pneumocystis carinii pneumonia -- Diagnosis ,Health ,Health care industry - Abstract
Pneumocystis carinii causes life-threatening pneumonitis (PCP) in immunocompromised individuals. In the non-AIDS (acquired immunodeficiency syndrome) population, PCP is frequently associated with corticosteroid therapy, and the rodent model uses corticosteroid-induced immunosuppression to provoke PCP. Although patients with intracranial tumors are frequently treated with long courses of corticosteroids, there have been very few descriptions of PCP in this population. We report the diagnosis and treatment of PCP in four patients over a 12-month poried with intracranial neoplasms who developed symptoms during corticosteroid taper. Effective prophylaxis against PCP exists and should be considered for patients with intracranial neoplasms receiving long-term steroids.
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- 1993
8. Therapeutic Advances in Neuro-Oncology.
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McFaline-Figueroa, J. Ricardo, Lee, Eudocia Q., and Wen, Patrick Y.
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- 2022
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9. Modified Criteria for Radiographic Response Assessment in Glioblastoma Clinical Trials.
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Ellingson, Benjamin, Wen, Patrick, Cloughesy, Timothy, Ellingson, Benjamin M, Wen, Patrick Y, and Cloughesy, Timothy F
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BRAIN tumor treatment ,GLIOMA treatment ,BRAIN ,BRAIN tumors ,CLINICAL trials ,DIAGNOSTIC imaging ,GLIOMAS ,MAGNETIC resonance imaging ,COMPUTERS in medicine ,TREATMENT effectiveness ,DISEASE progression - Abstract
Radiographic endpoints including response and progression are important for the evaluation of new glioblastoma therapies. The current RANO criteria was developed to overcome many of the challenges identified with previous guidelines for response assessment, however, significant challenges and limitations remain. The current recommendations build on the strengths of the current RANO criteria, while addressing many of these limitations. Modifications to the current RANO criteria include suggestions for volumetric response evaluation, use contrast enhanced T1 subtraction maps to increase lesion conspicuity, removal of qualitative non-enhancing tumor assessment requirements, use of the post-radiation time point as the baseline for newly diagnosed glioblastoma response assessment, and "treatment-agnostic" response assessment rubrics for identifying pseudoprogression, pseudoresponse, and a confirmed durable response in newly diagnosed and recurrent glioblastoma trials. [ABSTRACT FROM AUTHOR]
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- 2017
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10. Radiation therapy for glioblastoma: Executive summary of an American Society for Radiation Oncology Evidence-Based Clinical Practice Guideline.
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Cabrera, Alvin R., Kirkpatrick, John P., Fiveash, John B., Shih, Helen A., Koay, Eugene J., Lutz, Stephen, Petit, Joshua, Chao, Samuel T., Brown, Paul D., Vogelbaum, Michael, Reardon, David A., Chakravarti, Arnab, Wen, Patrick Y., and Chang, Eric
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Purpose To present evidence-based guidelines for radiation therapy in treating glioblastoma not arising from the brainstem. Methods and materials The American Society for Radiation Oncology (ASTRO) convened the Glioblastoma Guideline Panel to perform a systematic literature review investigating the following: (1) Is radiation therapy indicated after biopsy/resection of glioblastoma and how does systemic therapy modify its effects? (2) What is the optimal dose-fractionation schedule for external beam radiation therapy after biopsy/resection of glioblastoma and how might treatment vary based on pretreatment characteristics such as age or performance status? (3) What are ideal target volumes for curative-intent external beam radiation therapy of glioblastoma? (4) What is the role of reirradiation among glioblastoma patients whose disease recurs following completion of standard first-line therapy? Guideline recommendations were created using predefined consensus-building methodology supported by ASTRO-approved tools for grading evidence quality and recommendation strength. Results Following biopsy or resection, glioblastoma patients with reasonable performance status up to 70 years of age should receive conventionally fractionated radiation therapy (eg, 60 Gy in 2-Gy fractions) with concurrent and adjuvant temozolomide. Routine addition of bevacizumab to this regimen is not recommended. Elderly patients (≥ 70 years of age) with reasonable performance status should receive hypofractionated radiation therapy (eg, 40 Gy in 2.66-Gy fractions); preliminary evidence may support adding concurrent and adjuvant temozolomide to this regimen. Partial brain irradiation is the standard paradigm for radiation delivery. A variety of acceptable strategies exist for target volume definition, generally involving 2 phases (primary and boost volumes) or 1 phase (single volume). For recurrent glioblastoma, focal reirradiation can be considered in younger patients with good performance status. Conclusions Radiation therapy occupies an integral role in treating glioblastoma. Whether and how radiation therapy should be applied depends on characteristics specific to tumor and patient, including age and performance status. [ABSTRACT FROM AUTHOR]
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- 2016
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11. Reversed cerebral asymmetry in women with breast cancer
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Sandson, Thomas A., Wen, Patrick Y., and LeMay, Marjorie
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Breast cancer -- Research ,Symmetry (Biology) -- Health aspects ,Prenatal influences -- Research - Published
- 1992
12. ROAR trial: which treatment is effective after progression? - Authors' reply.
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Wen, Patrick Y, Burgess, Paul, Ilankumaran, Palanichamy, and Subbiah, Vivek
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AUTHORS , *THERAPEUTICS - Published
- 2022
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13. A Phase I Trial of Tipifarnib With Radiation Therapy, With and Without Temozolomide, for Patients With Newly Diagnosed Glioblastoma
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Nghiemphu, Phioanh Leia, Wen, Patrick Y., Lamborn, Kathleen R., Drappatz, Jan, Robins, H. Ian, Fink, Karen, Malkin, Mark G., Lieberman, Frank S., DeAngelis, Lisa M., Torres-Trejo, Alejandro, Chang, Susan M., Abrey, Lauren, Fine, Howard A., Demopoulos, Alexis, Lassman, Andrew B., Kesari, Santosh, Mehta, Minesh P., Prados, Michael D., and Cloughesy, Timothy F.
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GLIOBLASTOMA multiforme , *COHORT analysis , *ANTICONVULSANTS , *ASTROCYTOMAS , *ENZYME inhibitors , *RADIOTHERAPY , *PHYSIOLOGICAL effects of radiation , *DIAGNOSIS , *THERAPEUTICS - Abstract
Purpose: To determine the maximum tolerated dose (MTD) of tipifarnib in combination with conventional radiotherapy for patients with newly diagnosed glioblastoma. The MTD was evaluated in three patient cohorts, stratified based on concurrent use of enzyme-inducing antiepileptic drugs (EIAED) or concurrent treatment with temozolomide (TMZ): Group A: patients not receiving EIAED and not receiving TMZ; Group A-TMZ: patients not receiving EIAED and receiving treatment with TMZ; Group B: any patients receiving EIAED but not TMZ. Patients and Methods: After diagnostic surgery or biopsy, treatment with tipifarnib started 5 to 9 days before initiating radiotherapy, twice daily, in 4-week cycles using discontinuous dosing (21 out of 28 days), until toxicity or progression. For Group A-TMZ, patients also received TMZ daily during radiotherapy and then standard 5/28 days dosing after radiotherapy. Dose-limiting toxicity (DLT) was determined over the first 10 weeks of therapy for all cohorts. Results: Fifty-one patients were enrolled for MTD determination: 10 patients in Group A, 21 patients in Group A-TMZ, and 20 patients in Group B. In the Group A and Group A-TMZ cohorts, patients achieved the intended MTD of 300 mg twice daily (bid) with DLTs including rash and fatigue. For Group B, the MTD was determined as 300 mg bid, half the expected dose. The DLTs included rash and one intracranial hemorrhage. Thirteen of the 20 patients evaluated in Group A-TMZ were alive at 1 year. Conclusion: Tipifarnib is well tolerated at 300 mg bid given discontinuously (21/28 days) in 4-week cycles, concurrently with standard chemo/radiotherapy. A Phase II study should evaluate the efficacy of tipifarnib with radiation and TMZ in patients with newly diagnosed glioblastoma and not receiving EIAED. [Copyright &y& Elsevier]
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- 2011
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14. Antiangiogenic Strategies for Treatment of Malignant Gliomas
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Chi, Andrew S., Norden, Andrew D., and Wen, Patrick Y.
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ANTINEOPLASTIC agents ,GLIOBLASTOMA multiforme ,CANCER prognosis ,BRAIN cancer patients ,CLINICAL trials ,VASCULAR endothelial growth factor antagonists ,DIAGNOSIS - Abstract
Summary: Numerous antiangiogenic agents with diverse mechanisms of action are currently under investigation for the treatment of patients with glioblastoma (GBM), a diagnosis that continues to carry a poor prognosis despite maximal conventional therapy. Early clinical trials suggest that antiangiogenic drugs, which target the blood vessels of these highly angiogenic tumors, may have clinical benefit in GBM patients. Antiangiogenic agents have potent antiedema and steroid-sparing effects in patients, and emerging data suggest that these drugs may modestly improve progression-free survival. Although these early results are encouraging, several issues arise regarding the use and efficacy of these agents. Interpretation of the radiographic changes that occur after treatment with antiangiogenic agents presents a major challenge. Still lacking are reliable radiographic and biologic markers that can predict which patients will benefit from treatment and that accurately indicate response and progression during therapy. In addition, most patients treated with antiangiogenic drugs eventually progress, and the mechanisms by which tumors escape from therapy are only beginning to be understood. Larger prospective trials that incorporate correlative biomarker studies will be required to address these challenges. Here, we summarize the clinical experience with antiangiogenic therapy in patients with malignant gliomas (MG), review the major issues concerning the use and development of these agents, and discuss strategies that may build upon the initial gains observed with antiangiogenic agents. [Copyright &y& Elsevier]
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- 2009
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15. Functional drug susceptibility testing using single-cell mass predicts treatment outcome in patient-derived cancer neurosphere models.
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Stockslager, Max A., Malinowski, Seth, Touat, Mehdi, Yoon, Jennifer C., Geduldig, Jack, Mirza, Mahnoor, Kim, Annette S., Wen, Patrick Y., Chow, Kin-Hoe, Ligon, Keith L., and Manalis, Scott R.
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Functional precision medicine aims to match individual cancer patients to optimal treatment through ex vivo drug susceptibility testing on patient-derived cells. However, few functional diagnostic assays have been validated against patient outcomes at scale because of limitations of such assays. Here, we describe a high-throughput assay that detects subtle changes in the mass of individual drug-treated cancer cells as a surrogate biomarker for patient treatment response. To validate this approach, we determined ex vivo response to temozolomide in a retrospective cohort of 69 glioblastoma patient-derived neurosphere models with matched patient survival and genomics. Temozolomide-induced changes in cell mass distributions predict patient overall survival similarly to O
6 -methylguanine-DNA methyltransferase (MGMT) promoter methylation and may aid in predictions in gliomas with mismatch-repair variants of unknown significance, where MGMT is not predictive. Our findings suggest cell mass is a promising functional biomarker for cancers and drugs that lack genomic biomarkers. [Display omitted] • In a retrospective study, ex vivo drug testing predicts GBM patient survival • Testing is based on detecting subtle changes in single-cell mass • Predictive power of functional testing is comparable to MGMT promoter methylation • Mass biomarker could be used in situations where genomic biomarkers are unavailable Stockslager et al. find in a retrospective study that functional drug susceptibility testing predicts the response of patients with glioblastoma to chemotherapy. By detecting subtle changes in tumor cell mass after ex vivo drug exposure, treatment response can be predicted with power comparable to the standard-of-care genomic biomarker. [ABSTRACT FROM AUTHOR]- Published
- 2021
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16. Current drug development and trial designs in neuro-oncology: report from the first American Society of Clinical Oncology and Society for Neuro-Oncology Clinical Trials Conference.
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Rahman, Rifaquat, Polley, Mei-Yin C, Alder, Laura, Brastianos, Priscilla K, Anders, Carey K, Tawbi, Hussein A, Mehta, Minesh, Wen, Patrick Y, Geyer, Susan, de Groot, John, Zadeh, Gelareh, Piantadosi, Steven, Galanis, Evanthia, and Khasraw, Mustafa
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DRUG development , *CLINICAL trials , *DRUG discovery , *CENTRAL nervous system , *ONCOLOGY - Abstract
Successful drug development for people with cancers of the CNS has been challenging. There are multiple barriers to successful drug development including biological factors, rarity of the disease, and ineffective use of clinical trials. Based upon a series of presentations at the First Central Nervous System Clinical Trials Conference hosted by the American Society of Clinical Oncology and the Society for Neuro-Oncology, we provide an overview on drug development and novel trial designs in neuro-oncology. This Review discusses the challenges of therapeutic development in neuro-oncology and proposes strategies to improve the drug discovery process by enriching the pipeline of promising therapies, optimising trial design, incorporating biomarkers, using external data, and maximising efficacy and reproducibility of clinical trials. [ABSTRACT FROM AUTHOR]
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- 2023
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17. Incidence and Predictors of Neurologic Death in Patients with Brain Metastases.
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Reese, R. Alexander, Lamba, Nayan, Catalano, Paul J., Cagney, Daniel N., Wen, Patrick Y., and Aizer, Ayal A.
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BRAIN death , *SMALL cell lung cancer , *HER2 positive breast cancer , *KARNOFSKY Performance Status , *UVEA cancer , *GASTROINTESTINAL cancer - Abstract
Neurologic death is the most serious consequence of intracranial disease among patients with brain metastases. Identifying patients with brain metastases at increased risk of neurologic death can improve care and guide further research. We sought to delineate factors predictive of neurologic death among patients with brain metastases. We identified 1218 patients with newly diagnosed brain metastases managed at Brigham and Women's Hospital/Dana-Farber Cancer Institute from 2008–2015. Factors predictive of neurologic death were assessed via univariable and multivariable Fine and Gray competing risks regression. On multivariable analysis, neurologic death was associated with number of brain metastases (hazard ratio [HR] 1.01 per 1 metastasis increase, 95% confidence interval [CI] 1.01–1.02, P < 0.001) and 3 primary tumor sites (reference=non-small cell lung cancer): melanoma (HR 4.67, 95% CI 3.27–6.68, P < 0.001), small cell lung cancer (HR 2.33, 95% CI 1.47–3.68, P < 0.001), and gastrointestinal cancer (HR 2.21, 95% CI 1.28–3.82, P = 0.005). Conversely, a reduction in neurologic death was found in patients with good Karnofsky performance status (90–100 vs. 30-80, HR 0.67, 95% CI 0.48–0.95, P = 0.03) and progressive extracranial metastases at diagnosis of intracranial disease (HR 0.50, 95% CI 0.38–0.67, P = 0.001). Among patients with breast primaries, HER2+ patients displayed increased neurologic death relative to the reference of HR+/HER2– (univariable analysis only: HR 2.41, 95% CI 1.00–5.84, P = 0.05). Patients with melanoma, small cell lung cancer, gastrointestinal cancer, and HER2+ breast cancer primaries, as well as greater intracranial versus extracranial disease burden, harbor significant risk of neurologic death. Future research investigating novel intracranial approaches should focus on these populations. [ABSTRACT FROM AUTHOR]
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- 2022
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18. Therapeutic avenues for cancer neuroscience: translational frontiers and clinical opportunities.
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Shi, Diana D, Guo, Jimmy A, Hoffman, Hannah I, Su, Jennifer, Mino-Kenudson, Mari, Barth, Jaimie L, Schenkel, Jason M, Loeffler, Jay S, Shih, Helen A, Hong, Theodore S, Wo, Jennifer Y, Aguirre, Andrew J, Jacks, Tyler, Zheng, Lei, Wen, Patrick Y, Wang, Timothy C, and Hwang, William L
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NERVOUS system , *TUMOR microenvironment , *TUMOR growth , *NEUROSCIENCES , *NEURALGIA - Abstract
With increasing attention on the essential roles of the tumour microenvironment in recent years, the nervous system has emerged as a novel and crucial facilitator of cancer growth. In this Review, we describe the foundational, translational, and clinical advances illustrating how nerves contribute to tumour proliferation, stress adaptation, immunomodulation, metastasis, electrical hyperactivity and seizures, and neuropathic pain. Collectively, this expanding knowledge base reveals multiple therapeutic avenues for cancer neuroscience that warrant further exploration in clinical studies. We discuss the available clinical data, including ongoing trials investigating novel agents targeting the tumour-nerve axis, and the therapeutic potential for repurposing existing neuroactive drugs as an anti-cancer approach, particularly in combination with established treatment regimens. Lastly, we discuss the clinical challenges of these treatment strategies and highlight unanswered questions and future directions in the burgeoning field of cancer neuroscience. [ABSTRACT FROM AUTHOR]
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- 2022
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19. RTOG 0913: A Phase 1 Study of Daily Everolimus (RAD001) in Combination With Radiation Therapy and Temozolomide in Patients With Newly Diagnosed Glioblastoma.
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Chinnaiyan, Prakash, Won, Minhee, Wen, Patrick Y., Rojiani, Amyn M., Wendland, Merideth, Dipetrillo, Thomas A., Corn, Benjamin W., and Mehta, Minesh P.
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CANCER radiotherapy , *GLIOBLASTOMA multiforme treatment , *RAPAMYCIN , *ALKYLATING agents , *DRUG dosage , *HYPERCHOLESTEREMIA - Abstract
Purpose: To determine the safety of the mammalian target of rapamycin inhibitor everolimus (RAD001) administered daily with concurrent radiation and temozolomide in newly diagnosed glioblastoma patients. Methods and Materials: Everolimus was administered daily with concurrent radiation (60 Gy in 30 fractions) and temozolomide (75 mg/m2 per day). Everolimus was escalated from 2.5 mg/d (dose level 1) to 5 mg/d (dose level 2) to 10 mg/d (dose level 3). Adjuvant temozolomide was delivered at 150 to 200 mg/m2 on days 1 to 5, every 28 days, for up to 12 cycles, with concurrent everolimus at the previously established daily dose of 10 mg/d. Dose escalation continued if a dose level produced dose-limiting toxicities (DLTs) in fewer than 3 of the first 6 evaluable patients. Results: Between October 28, 2010, and July 2, 2012, the Radiation Therapy Oncology Group 0913 protocol initially registered a total of 35 patients, with 25 patients successfully meeting enrollment criteria receiving the drug and evaluable for toxicity. Everolimus was successfully escalated to the predetermined maximum tolerated dose of 10 mg/d. Two of the first 6 eligible patients had a DLT at each dose level. DLTs included gait disturbance, febrile neutropenia, rash, fatigue, thrombocytopenia, hypoxia, ear pain, headache, and mucositis. Other common toxicities were grade 1 or 2 hypercholesterolemia and hypertriglyceridemia. At the time of analysis, there was 1 death reported, which was attributed to tumor progression. Conclusions: Daily oral everolimus (10 mg) combined with both concurrent radiation and temozolomide followed by adjuvant temozolomide is well tolerated, with an acceptable toxicity profile. A randomized phase 2 clinical trial with mandatory correlative biomarker analysis is currently under way, designed to both determine the efficacy of this regimen and identify molecular determinants of response. [ABSTRACT FROM AUTHOR]
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- 2013
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20. Novel anti-angiogenic therapies for malignant gliomas
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Norden, Andrew D, Drappatz, Jan, and Wen, Patrick Y
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GLIOMA treatment , *RADIOTHERAPY , *DRUG therapy , *VASCULAR endothelial growth factors , *NEOVASCULARIZATION , *BEVACIZUMAB - Abstract
Summary: Background: Despite optimum treatment with surgery, radiation therapy, and chemotherapy, most patients with malignant glioma have a poor prognosis. Malignant gliomas are vascular tumours that produce vascular endothelial growth factor (VEGF), which is an important mediator of angiogenesis. Preclinical data indicate that angiogenesis is essential for the proliferation and survival of malignant glioma cells, which suggests that inhibition of angiogenesis might be an effective therapeutic strategy. Anti-angiogenic therapies that target VEGF and the VEGF receptor (VEGFR) are effective adjuncts to the treatment of solid tumours. Normalisation of dilated and leaky tumour vasculature might also enable anti-angiogenic therapy to increase the efficacy of radiation therapy and cytotoxic chemotherapy. Recent developments: Several studies have investigated the use of bevacizumab—a humanised monoclonal antibody against VEGF—for patients with recurrent malignant glioma. Treatment with bevacizumab is commonly combined with cytotoxic chemotherapy and results in dramatic responses seen on radiographs, prolongation of progression-free survival, and less need for corticosteroids. Similar results have been shown with small-molecule inhibitors of VEGFR, such as cediranib. Anti-angiogenic treatment is generally well tolerated but common adverse effects include hypertension and proteinuria, whereas the potentially more serious adverse effects, such as thromboembolic disease and haemorrhage, occur infrequently. At least half of patients fail to respond to anti-angiogenic treatment and the response duration is variable. Resistance to anti-angiogenic therapy might implicate alternative pro-angiogenic factors, such as basic fibroblast growth factor, stromal-derived factor-1α, the angiopoietin receptor Tie2, and placental growth factor. Anti-angiogenic therapy might also lead to mobilisation of circulating endothelial cells towards the tumour, which supports angiogenesis. Another possible mechanism of resistance of malignant glioma cells might be upregulation of pro-invasive molecules, which would result in increased infiltrative tumour growth along the blood vessels. Where next?: Although anti-angiogenic therapies are promising, the duration of response with available regimens is modest. Continuing investigations will determine whether these drugs are best used for newly diagnosed or recurrent tumours and will establish the optimum combinations with radiation, cytotoxic chemotherapy, and other targeted molecular compounds. As yet, there are no effective treatments for patients on anti-angiogenic therapies whose tumours progress. Further understanding of the mechanisms of resistance to anti-angiogenic therapies and better selection of patients will be crucial to improve outcomes for patients with malignant glioma. [Copyright &y& Elsevier]
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- 2008
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21. Leveraging external data in the design and analysis of clinical trials in neuro-oncology.
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Rahman, Rifaquat, Ventz, Steffen, McDunn, Jon, Louv, Bill, Reyes-Rivera, Irmarie, Polley, Mei-Yin C, Merchant, Fahar, Abrey, Lauren E, Allen, Joshua E, Aguilar, Laura K, Aguilar-Cordova, Estuardo, Arons, David, Tanner, Kirk, Bagley, Stephen, Khasraw, Mustafa, Cloughesy, Timothy, Wen, Patrick Y, Alexander, Brian M, and Trippa, Lorenzo
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EXPERIMENTAL design , *DATA analysis , *INFORMATION sharing , *OPTIMAL stopping (Mathematical statistics) , *RESEARCH institutes - Abstract
Integration of external control data, with patient-level information, in clinical trials has the potential to accelerate the development of new treatments in neuro-oncology by contextualising single-arm studies and improving decision making (eg, early stopping decisions). Based on a series of presentations at the 2020 Clinical Trials Think Tank hosted by the Society of Neuro-Oncology, we provide an overview on the use of external control data representative of the standard of care in the design and analysis of clinical trials. High-quality patient-level records, rigorous methods, and validation analyses are necessary to effectively leverage external data. We review study designs, statistical methods, risks, and potential distortions in using external data from completed trials and real-world data, as well as data sources, data sharing models, ongoing work, and applications in glioblastoma. [ABSTRACT FROM AUTHOR]
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- 2021
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22. Prediction of Outcomes with a Computational Biology Model in Newly Diagnosed Glioblastoma Patients Treated with Radiation Therapy and Temozolomide.
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Rahman, Rifaquat, Trippa, Lorenzo, Alden, Stephanie, Fell, Geoffrey, Abbasi, Taher, Mundkur, Yatin, Singh, Neeraj K., Talawdekar, Anay, Husain, Zakir, Vali, Shireen, Ligon, Keith L., Wen, Patrick Y., and Alexander, Brian M.
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COMPUTATIONAL biology , *GLIOBLASTOMA multiforme , *FORECASTING , *RADIOTHERAPY , *TEMOZOLOMIDE , *OLIGODENDROGLIOMAS , *GLIOMA treatment , *BRAIN tumor treatment , *THERAPEUTIC use of antineoplastic agents , *BIOLOGICAL models , *RESEARCH , *GENETIC mutation , *RESEARCH methodology , *GLIOMAS , *RETROSPECTIVE studies , *MEDICAL cooperation , *EVALUATION research , *BRAIN tumors , *TREATMENT effectiveness , *BIOINFORMATICS , *COMPARATIVE studies , *SURVIVAL analysis (Biometry) , *GENOTYPES , *COMBINED modality therapy , *PROPORTIONAL hazards models - Abstract
Purpose: Precision medicine has been most successful in targeting single mutations, but personalized medicine using broader genomic tumor profiles for individual patients is less well developed. We evaluate a genomics-informed computational biology model (CBM) to predict outcomes from standard treatments and to suggest novel therapy recommendations in glioblastoma (GBM).Methods and Materials: In this retrospective study, 98 patients with newly diagnosed GBM undergoing surgery followed by radiation therapy and temozolomide at a single institution with available genomic data were identified. Incorporating mutational and copy number aberration data, a CBM was used to simulate the response of GBM tumor cells and generate efficacy predictions for radiation therapy (RTeff) and temozolomide (TMZeff). RTeff and TMZeff were evaluated for association with overall survival and progression-free survival in a Cox regression model. To demonstrate a CBM-based individualized therapy strategy, treatment recommendations were generated for each patient by testing a panel of 45 central nervous system-penetrant US Food and Drug Administration-approved agents.Results: High RTeff scores were associated with longer survival on univariable analysis (P < .001), which persisted after controlling for age, extent of resection, performance status, MGMT, and IDH status (P = .017). High RTeff patients had a longer overall survival compared with low RTeff patients (median, 27.7 vs 14.6 months). High TMZeff was also associated with longer survival on univariable analysis (P = .007) but did not hold on multivariable analysis, suggesting an interplay with MGMT status. Among predictions of the 3 most efficacious combination therapies for each patient, only 2.4% (7 of 294) of 2-drug recommendations produced by the CBM included TMZ.Conclusions: CBM-based predictions of RT and TMZ effectiveness were associated with survival in patients with newly diagnosed GBM treated with those therapies, suggesting a possible predictive utility. Furthermore, the model was able to suggest novel individualized monotherapies and combinations. Prospective evaluation of such a personalized treatment strategy in clinical trials is needed. [ABSTRACT FROM AUTHOR]- Published
- 2020
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23. Dabrafenib plus trametinib in patients with BRAFV600E-mutated biliary tract cancer (ROAR): a phase 2, open-label, single-arm, multicentre basket trial.
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Subbiah, Vivek, Lassen, Ulrik, Élez, Elena, Italiano, Antoine, Curigliano, Giuseppe, Javle, Milind, de Braud, Filippo, Prager, Gerald W, Greil, Richard, Stein, Alexander, Fasolo, Angelica, Schellens, Jan H M, Wen, Patrick Y, Viele, Kert, Boran, Aislyn D, Gasal, Eduard, Burgess, Paul, Ilankumaran, Palanichamy, and Wainberg, Zev A
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DEATH rate , *BRAF genes , *BILIARY tract , *GENETIC mutation , *PYRIDINE , *RESEARCH , *CLINICAL trials , *HETEROCYCLIC compounds , *RESEARCH methodology , *PROGNOSIS , *CANCER relapse , *ANTINEOPLASTIC agents , *EVALUATION research , *MEDICAL cooperation , *AMINES , *IMIDAZOLES , *TREATMENT effectiveness , *COMPARATIVE studies , *TRANSFERASES , *RESEARCH funding ,BILIARY tract cancer ,BILE duct tumors - Abstract
Background: Effective treatments for patients with cholangiocarcinoma after progression on gemcitabine-based chemotherapy are urgently needed. Mutations in the BRAF gene have been found in 5% of biliary tract tumours. The combination of dabrafenib and trametinib has shown activity in several BRAFV600E-mutated cancers. We aimed to assess the activity and safety of dabrafenib and trametinib combination therapy in patients with BRAFV600E-mutated biliary tract cancer.Methods: This study is part of an ongoing, phase 2, open-label, single-arm, multicentre, Rare Oncology Agnostic Research (ROAR) basket trial in patients with BRAFV600E-mutated rare cancers. Patients were eligible for the biliary tract cancer cohort if they were aged 18 years or older, had BRAFV600E-mutated, unresectable, metastatic, locally advanced, or recurrent biliary tract cancer, an Eastern Cooperative Oncology Group performance status of 0-2, and had received previous systemic treatment. All patients were treated with oral dabrafenib 150 mg twice daily and oral trametinib 2 mg once daily until disease progression or intolerance of treatment. The primary endpoint was the overall response rate, which was determined by Response Evaluation Criteria in Solid Tumors version 1.1 in the intention-to-treat evaluable population, which comprised all enrolled patients regardless of receiving treatment who were evaluable (ie, had progression, began a new anticancer treatment, withdrew consent, died, had stable disease for 6 weeks or longer, or had two or more post-baseline assessments). The ROAR trial is registered with ClinicalTrials.gov, NCT02034110. These results are based on an interim analysis; the study is active but not recruiting.Findings: Between March 12, 2014, and July 18, 2018, 43 patients with BRAFV600E-mutated biliary tract cancer were enrolled to the study and were evaluable. Median follow-up was 10 months (IQR 6-15). An investigator-assessed overall response was achieved by 22 (51%, 95% CI 36-67) of 43 patients. An independent reviewer-assessed overall response was achieved by 20 (47%, 95% CI 31-62) of 43 patients. The most common grade 3 or worse adverse event was increased γ-glutamyltransferase in five (12%) patients. 17 (40%) patients had serious adverse events and nine (21%) had treatment-related serious adverse events, the most frequent of which was pyrexia (eight [19%]). No treatment-related deaths were reported.Interpretation: Dabrafenib plus trametinib combination treatment showed promising activity in patients with BRAFV600E-mutated biliary tract cancer, with a manageable safety profile. Routine testing for BRAFV600E mutations should be considered in patients with biliary tract cancer.Funding: GlaxoSmithKline and Novartis. [ABSTRACT FROM AUTHOR]- Published
- 2020
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24. Response assessment in paediatric high-grade glioma: recommendations from the Response Assessment in Pediatric Neuro-Oncology (RAPNO) working group.
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Erker, Craig, Tamrazi, Benita, Poussaint, Tina Y, Mueller, Sabine, Mata-Mbemba, Daddy, Franceschi, Enrico, Brandes, Alba A, Rao, Arvind, Haworth, Kellie B, Wen, Patrick Y, Goldman, Stewart, Vezina, Gilbert, MacDonald, Tobey J, Dunkel, Ira J, Morgan, Paul S, Jaspan, Tim, Prados, Michael D, and Warren, Katherine E
- Abstract
Response criteria for paediatric high-grade glioma vary historically and across different cooperative groups. The Response Assessment in Neuro-Oncology working group developed response criteria for adult high-grade glioma, but these were not created to meet the unique challenges in children with the disease. The Response Assessment in Pediatric Neuro-Oncology (RAPNO) working group, consisting of an international panel of paediatric and adult neuro-oncologists, clinicians, radiologists, radiation oncologists, and neurosurgeons, was established to address issues and unique challenges in assessing response in children with CNS tumours. We established a subcommittee to develop response assessment criteria for paediatric high-grade glioma. Current practice and literature were reviewed to identify major challenges in assessing the response of paediatric high-grade gliomas to various treatments. For areas in which scientific investigation was scarce, consensus was reached through an iterative process. RAPNO response assessment recommendations include the use of MRI of the brain and the spine, assessment of clinical status, and the use of corticosteroids or antiangiogenics. Imaging standards for brain and spine are defined. Compared with the recommendations for the management of adult high-grade glioma, for paediatrics there is inclusion of diffusion-weighted imaging and a higher reliance on T2-weighted fluid-attenuated inversion recovery. Consensus recommendations and response definitions have been established and, similar to other RAPNO recommendations, prospective validation in clinical trials is warranted. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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25. Glioma patient-reported outcome assessment in clinical care and research: a Response Assessment in Neuro-Oncology collaborative report.
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Armstrong, Terri S, Dirven, Linda, Arons, David, Bates, Amanda, Chang, Susan M, Coens, Corneel, Espinasse, Claire, Gilbert, Mark R, Jenkinson, David, Kluetz, Paul, Mendoza, Tito, Rubinstein, Larry, Sul, Joohee, Weller, Michael, Wen, Patrick Y, van den Bent, Martin J, and Taphoorn, Martin J B
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GLIOMAS , *CLINICAL trials , *LITERATURE reviews , *TRIAL practice , *COMPUTER surveys - Abstract
Clinical trials of treatments for high-grade gliomas have traditionally relied on measures of response or time-dependent metrics; however, these endpoints have limitations because they do not characterise the functional or symptomatic effect of the condition on the person. Including clinical outcome assessments, such as patient- reported outcomes (PROs), to determine net clinical benefit of a treatment strategy is needed because of the substantial burden of symptoms and impaired functioning in this patient population. The US National Cancer Institute convened a meeting to review previous recommendations and existing PRO measures of symptoms and function that can be applied to current trials and clinical practice for high-grade gliomas. Measures were assessed for relevance, relationship to disease and therapy, sensitivity to change, psychometric properties, response format, patient acceptability, and use of self-report. The group also relied on patient input including the results of an online survey, a literature review on available clinical outcomes, expert opinion, and alignment with work done by other organisations. A core set of priority constructs was proposed that allows more comprehensive evaluation of therapies and comparison of outcomes among studies, and enhances efforts to improve the measurement of these core clinical outcomes. The proposed set of constructs was then presented to the Society for Neuro-Oncology Response Assessment in Neuro-Oncology Working Group and feedback was solicited. [ABSTRACT FROM AUTHOR]
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- 2020
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26. Working plan for the use of patient-reported outcome measures in adults with brain tumours: a Response Assessment in Neuro-Oncology (RANO) initiative.
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Dirven, Linda, Armstrong, Terri S, Blakeley, Jaishri O, Brown, Paul D, Grant, Robin, Jalali, Rakesh, Leeper, Heather, Mendoza, Tito, Nayak, Lakshmi, Reijneveld, Jaap C, Rhun, Emilie Le, Walbert, Tobias, Weller, Michael, Wen, Patrick Y, Taphoorn, Martin J B, and Le Rhun, Emilie
- Abstract
The Response Assessment in Neuro-Oncology-Patient-Reported Outcome (RANO-PRO) working group is an international multidisciplinary collaboration that provides guidance on the use of patient-reported outcome (PRO) measures in clinical trials and practice for adult patients with brain tumours. Findings from both PROs and traditional outcome measures, such as survival, and clinical or radiological response, are essential to inform the research community, policy makers, physicians, and patients in the treatment decision-making process. Previous initiatives in oncology have focused on guidelines concerning the collection, analysis, interpretation, and reporting of PRO data. However, we recommend the application of appropriate PRO instruments, with respect to its content and measurement properties (ie, research question, content validity, and other measurement properties), in brain tumour research. PROs should be well defined and reliable to generate high-quality evidence, and our recommendations on the use of specific PRO measures could help to improve the quality of PRO evidence derived from neuro-oncological studies, and might add a new dimension in how the value of therapeutics is assessed in patients with brain tumours. In this Policy Review, we present the RANO-PRO working plan for the use of PROs in adults with brain tumours. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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27. Clinical trial design for local therapies for brain metastases: a guideline by the Response Assessment in Neuro-Oncology Brain Metastases working group.
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Alexander, Brian M, Brown, Paul D, Ahluwalia, Manmeet S, Aoyama, Hidefumi, Baumert, Brigitta G, Chang, Susan M, Gaspar, Laurie E, Kalkanis, Steven N, Macdonald, David R, Mehta, Minesh P, Soffietti, Riccardo, Suh, John H, van den Bent, Martin J, Vogelbaum, Michael A, Wefel, Jeffrey S, Lee, Eudocia Q, Wen, Patrick Y, and Response Assessment in Neuro-Oncology (RANO) group
- Abstract
The goals of therapeutic and biomarker development form the foundation of clinical trial design, and change considerably from early-phase to late-phase trials. From these goals, decisions on specific clinical trial design elements, such as endpoint selection and statistical approaches, are formed. Whereas early-phase trials might focus on finding a therapeutic signal to make decisions on further development, late-phase trials focus on the confirmation of therapeutic impact by considering clinically meaningful endpoints. In this guideline from the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) working group, we highlight issues related to, and provide recommendations for, the design of clinical trials on local therapies for CNS metastases from solid tumours. We discuss endpoint selection criteria, the analysis appropriate for early-phase and late-phase trials, the association between tumour-specific and clinically meaningful endpoints, and possible issues related to the estimation of local control in the context of competing risks. In light of these discussions, we make specific recommendations on the clinical trial design of local therapies for brain metastases. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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28. Clinical trial design for systemic agents in patients with brain metastases from solid tumours: a guideline by the Response Assessment in Neuro-Oncology Brain Metastases working group.
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Camidge, D Ross, Lee, Eudocia Q, Lin, Nancy U, Margolin, Kim, Ahluwalia, Manmeet S, Bendszus, Martin, Chang, Susan M, Dancey, Janet, de Vries, Elisabeth G E, Harris, Gordon J, Hodi, F Stephen, Lassman, Andrew B, Macdonald, David R, Peereboom, David M, Schiff, David, Soffietti, Ricardo, van den Bent, Martin J, Wefel, Jeffrey S, and Wen, Patrick Y
- Abstract
Patients with active CNS disease are often excluded from clinical trials, and data regarding the CNS efficacy of systemic agents are usually obtained late in the drug development process or not at all. In this guideline from the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) working group, we provide detailed recommendations on when patients with brain metastases from solid tumours should be included or excluded in clinical trials of systemic agents. We also discuss the limitations of retrospective studies in determining the CNS efficacy of systemic drugs. Inclusion of patients with brain metastases early on in the clinical development of a drug or a regimen is needed to generate appropriate CNS efficacy or non-efficacy signals. We consider how to optimally incorporate or exclude such patients in systemic therapy trials depending on the likelihood of CNS activity of the agent by considering three scenarios: drugs that are considered very unlikely to have CNS antitumour activity or efficacy; drugs that are considered very likely to have CNS activity or efficacy; and drugs with minimal baseline information on CNS activity or efficacy. We also address trial design issues unique to patients with brain metastases, including the selection of appropriate CNS endpoints in systemic therapy trials. [ABSTRACT FROM AUTHOR]
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- 2018
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29. Hypofractionated Versus Standard Radiation Therapy With or Without Temozolomide for Older Glioblastoma Patients.
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Arvold, Nils D., Tanguturi, Shyam K., Aizer, Ayal A., Wen, Patrick Y., Reardon, David A., Lee, Eudocia Q., Nayak, Lakshmi, Christianson, Laura W., Horvath, Margaret C., Dunn, Ian F., Golby, Alexandra J., Johnson, Mark D., Claus, Elizabeth B., Chiocca, E. Antonio, Ligon, Keith L., and Alexander, Brian M.
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GLIOBLASTOMA multiforme , *GLIOBLASTOMA multiforme treatment , *TEMOZOLOMIDE , *OLDER patients , *CANCER radiotherapy , *RETROSPECTIVE studies , *DIAGNOSIS - Abstract
Purpose Older patients with newly diagnosed glioblastoma have poor outcomes, and optimal treatment is controversial. Hypofractionated radiation therapy (HRT) is frequently used but has not been compared to patients receiving standard fractionated radiation therapy (SRT) and temozolomide (TMZ). Methods and Materials We conducted a retrospective analysis of patients ≥65 years of age who received radiation for the treatment of newly diagnosed glioblastoma from 1994 to 2013. The distribution of clinical covariates across various radiation regimens was analyzed for possible selection bias. Survival was calculated using the Kaplan-Meier method. Comparison of hypofractionated radiation (typically, 40 Gy/15 fractions) versus standard fractionation (typically, 60 Gy/30 fractions) in the setting of temozolomide was conducted using Cox regression and propensity score analysis. Results Patients received SRT + TMZ (n=57), SRT (n=35), HRT + TMZ (n=34), or HRT (n=9). Patients receiving HRT were significantly older (median: 79 vs 69 years of age; P <.001) and had worse baseline performance status ( P <.001) than those receiving SRT. On multivariate analysis, older age (adjusted hazard ratio [AHR]: 1.06; 95% confidence interval [CI]: 1.01-1.10, P =.01), lower Karnofsky performance status (AHR: 1.02; 95% CI: 1.01-1.03; P =.01), multifocal disease (AHR: 2.11; 95% CI: 1.23-3.61, P =.007), and radiation alone (vs SRT + TMZ; SRT: AHR: 1.72; 95% CI: 1.06-2.79; P =.03; HRT: AHR: 3.92; 95% CI: 1.44-10.60, P =.007) were associated with decreased overall survival. After propensity score adjustment, patients receiving HRT with TMZ had similar overall survival compared with those receiving SRT with TMZ (AHR: 1.10, 95% CI: 0.50-2.4, P =.82). Conclusions With no randomized data demonstrating equivalence between HRT and SRT in the setting of TMZ for glioblastoma, significant selection bias exists in the implementation of HRT. Controlling for this bias, we observed similar overall survival for HRT and SRT with concurrent TMZ among elderly patients, suggesting the need for a randomized trial to compare these regimens directly. [ABSTRACT FROM AUTHOR]
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- 2015
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30. Phase I Study of Vandetanib With Radiotherapy and Temozolomide for Newly Diagnosed Glioblastoma
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Drappatz, Jan, Norden, Andrew D., Wong, Eric T., Doherty, Lisa M., LaFrankie, Debra C., Ciampa, Abigail, Kesari, Santosh, Sceppa, Christine, Gerard, Mary, Phan, Phuong, Schiff, David, Batchelor, Tracy T., Ligon, Keith L., Young, Geoffrey, Muzikansky, Alona, Weiss, Stephanie E., and Wen, Patrick Y.
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GLIOBLASTOMA multiforme , *CANCER radiotherapy , *CANCER chemotherapy , *VASCULAR endothelial growth factor antagonists , *EPIDERMAL growth factor , *ADJUVANT treatment of cancer , *ANTICONVULSANTS , *ENZYME inhibitors , *PATIENTS - Abstract
Purpose: Increasing evidence has suggested that angiogenesis inhibition might potentiate the effects of radiotherapy and chemotherapy in patients with glioblastoma (GBM). In addition, epidermal growth factor receptor inhibition might be of therapeutic benefit, because the epidermal growth factor receptor is upregulated in GBM and contributes to radiation resistance. We conducted a Phase I study of vandetanib, an inhibitor of vascular endothelial growth factor receptor 2 and epidermal growth factor receptor, in patients with newly diagnosed GBM combined with RT and temozolomide (TMZ). Methods and Materials: A total of 13 GBM patients were treated with vandetanib, radiotherapy, and concurrent and adjuvant TMZ, using a standard “3 + 3” dose escalation. The maximal tolerated dose was defined as the dose with <1 of 6 dose-limiting toxicities during the first 12 weeks of therapy. The eligible patients were adults with newly diagnosed GBM, Karnofsky performance status of ≥60, normal organ function, who were not taking enzyme-inducing antiepileptic drugs. Results: Of the 13 patients, 6 were treated with vandetanib at a dose of 200mg daily. Of the 6 patients, 3 developed dose-limiting toxicities within the first 12 weeks, including gastrointestinal hemorrhage and thrombocytopenia in 1 patient, neutropenia in 1 patient, and diverticulitis with gastrointestinal perforation in 1 patient. The other 7 patients were treated with 100 mg daily, with no dose-limiting toxicities observed, establishing this dose as the maximal tolerated dose combined with TMZ and RT. Conclusion: Vandetanib can be safely combined with RT and TMZ in GBM patients. A Phase II study in which patients are randomized to vandetanib 100 mg daily with RT and TMZ or RT and TMZ alone is underway. [ABSTRACT FROM AUTHOR]
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- 2010
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31. A Pilot Safety Study of Lenalidomide and Radiotherapy for Patients With Newly Diagnosed Glioblastoma Multiforme
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Drappatz, Jan, Wong, Eric T., Schiff, David, Kesari, Santosh, Batchelor, Tracy T., Doherty, Lisa, LaFrankie, Debra Conrad, Ramakrishna, Naren, Weiss, Stephanie, Smith, Sharon T., Ciampa, Abigail, Zimmerman, Jennifer, Ostrowsky, Louis, David, Karly, Norden, Andrew, Barron, Loretta, Sceppa, Christine, Black, Peter M., and Wen, Patrick Y.
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THALIDOMIDE , *GLIOBLASTOMA multiforme , *CANCER radiotherapy , *CANCER treatment , *IMMUNOLOGICAL adjuvants , *NEOVASCULARIZATION inhibitors , *PNEUMONIA , *PATIENTS - Abstract
Purpose: To define the maximum tolerated dose (MTD) of lenalidomide, an analogue of thalidomide with enhanced immunomodulatory and antiangiogenic properties and a more favorable toxicity profile, in patients with newly diagnosed glioblastoma multiforme (GBM) when given concurrently with radiotherapy. Patients and Methods: Patients with newly diagnosed GBM received radiotherapy concurrently with lenalidomide given for 3 weeks followed by a 1-week rest period and continued lenalidomide until tumor progression or unacceptable toxicity. Dose escalation occurred in groups of 6. Determination of the MTD was based on toxicities during the first 12 weeks of therapy. The primary endpoint was toxicity. Results: Twenty-three patients were enrolled, of whom 20 were treated and evaluable for both toxicity and tumor response and 2 were evaluable for toxicity only. Common toxicities included venous thromboembolic disease, fatigue, and nausea. Dose-limiting toxicities were eosinophilic pneumonitis and transaminase elevations. The MTD for lenalidomide was determined to be 15 mg/m2/d. Conclusion: The recommended dose for lenalidomide with radiotherapy is 15 mg/m2/d for 3 weeks followed by a 1-week rest period. Venous thromboembolic complications occurred in 4 patients, and prophylactic anticoagulation should be considered. [Copyright &y& Elsevier]
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- 2009
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32. AZD2171, a Pan-VEGF Receptor Tyrosine Kinase Inhibitor, Normalizes Tumor Vasculature and Alleviates Edema in Glioblastoma Patients
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Batchelor, Tracy T., Sorensen, A. Gregory, di Tomaso, Emmanuelle, Zhang, Wei-Ting, Duda, Dan G., Cohen, Kenneth S., Kozak, Kevin R., Cahill, Daniel P., Chen, Poe-Jou, Zhu, Mingwang, Ancukiewicz, Marek, Mrugala, Maciej M., Plotkin, Scott, Drappatz, Jan, Louis, David N., Ivy, Percy, Scadden, David T., Benner, Thomas, Loeffler, Jay S., and Wen, Patrick Y.
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GLIOBLASTOMA multiforme , *TUMORS , *PROTEIN-tyrosine kinase inhibitors , *VASCULAR endothelial growth factors , *EDEMA - Abstract
Summary: Using MRI techniques, we show here that normalization of tumor vessels in recurrent glioblastoma patients by daily administration of AZD2171—an oral tyrosine kinase inhibitor of VEGF receptors—has rapid onset, is prolonged but reversible, and has the significant clinical benefit of alleviating edema. Reversal of normalization began by 28 days, though some features persisted for as long as four months. Basic FGF, SDF1α, and viable circulating endothelial cells (CECs) increased when tumors escaped treatment, and circulating progenitor cells (CPCs) increased when tumors progressed after drug interruption. Our study provides insight into different mechanisms of action of this class of drugs in recurrent glioblastoma patients and suggests that the timing of combination therapy may be critical for optimizing activity against this tumor. [Copyright &y& Elsevier]
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- 2007
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33. 18. ALLELE: A consortium for prospective genomics and functional diagnostics to guide patient care and trial analysis in newly-diagnosed glioblastoma.
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Dubuc, Adrian M., Touat, Mehdi, Meredith, David M., Geduldig, Jack E., Santagata, Sandro, Ligon, Keith L., Schiff, David, Ahluwalia, Manmeet, Colman, Howard, Drappatz, Jann, Alexander, Brian M., Gaffey, Sarah C., Wen, Patrick Y., Ramkissoon, Shakt, de Groot, John F., Galanis, Evanthia, Lassman, Andrew B., Nabors, Burt, Arrilaga-Romany, Isabel, and Chiocca, E. Antonio
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GLIOBLASTOMA multiforme , *SINGLE nucleotide polymorphisms , *LYMPHOBLASTIC leukemia , *LYMPHOBLASTIC leukemia treatment , *NUCLEIC acid isolation methods , *EXOMES , *DIAGNOSIS , *CANCER risk factors - Published
- 2018
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34. Immunotherapy response assessment in neuro-oncology: a report of the RANO working group.
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Okada, Hideho, Weller, Michael, Huang, Raymond, Finocchiaro, Gaetano, Gilbert, Mark R, Wick, Wolfgang, Ellingson, Benjamin M, Hashimoto, Naoya, Pollack, Ian F, Brandes, Alba A, Franceschi, Enrico, Herold-Mende, Christel, Nayak, Lakshmi, Panigrahy, Ashok, Pope, Whitney B, Prins, Robert, Sampson, John H, Wen, Patrick Y, and Reardon, David A
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IMMUNOTHERAPY , *INFLAMMATION , *CANCER invasiveness , *IMMUNE response , *FOLLOW-up studies (Medicine) , *ADRENOCORTICAL hormones , *ALGORITHMS , *NERVOUS system tumors , *MEDICAL protocols , *RESEARCH funding , *DISEASE progression , *DIAGNOSIS , *TUMOR treatment - Abstract
Immunotherapy is a promising area of therapy in patients with neuro-oncological malignancies. However, early-phase studies show unique challenges associated with the assessment of radiological changes in response to immunotherapy reflecting delayed responses or therapy-induced inflammation. Clinical benefit, including long-term survival and tumour regression, can still occur after initial disease progression or after the appearance of new lesions. Refinement of the response assessment criteria for patients with neuro-oncological malignancies undergoing immunotherapy is therefore warranted. Herein, a multinational and multidisciplinary panel of neuro-oncology immunotherapy experts describe immunotherapy Response Assessment for Neuro-Oncology (iRANO) criteria based on guidance for the determination of tumour progression outlined by the immune-related response criteria and the RANO working group. Among patients who demonstrate imaging findings meeting RANO criteria for progressive disease within 6 months of initiating immunotherapy, including the development of new lesions, confirmation of radiographic progression on follow-up imaging is recommended provided that the patient is not significantly worse clinically. The proposed criteria also include guidelines for the use of corticosteroids. We review the role of advanced imaging techniques and the role of measurement of clinical benefit endpoints including neurological and immunological functions. The iRANO guidelines put forth in this Review will evolve successively to improve their usefulness as further experience from immunotherapy trials in neuro-oncology accumulate. [ABSTRACT FROM AUTHOR]
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- 2015
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35. Phase 2 trial design in neuro-oncology revisited: a report from the RANO group
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Galanis, Evanthia, Wu, Wenting, Cloughesy, Timothy, Lamborn, Kathleen, Mann, Bhupinder, Wen, Patrick Y, Reardon, David A, Wick, Wolfgang, Macdonald, David, Armstrong, Terri S, Weller, Michael, Vogelbaum, Michael, Colman, Howard, Sargent, Daniel J, van den Bent, Martin J, Gilbert, Mark, and Chang, Susan
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GLIOMA treatment , *BEVACIZUMAB , *BRAIN tumor treatment , *DRUG development , *THERAPEUTICS , *CLINICAL trials - Abstract
Summary: Advances in the management of gliomas, including the approval of agents such as temozolomide and bevacizumab, have created an evolving therapeutic landscape in glioma treatment, thus affecting our ability to reliably use historical controls to comparatively assess the activity of new therapies. Furthermore, the increasing availability of novel, targeted agents—which are competing for a small patient population, in view of the low incidence of primary brain tumours—draws attention to the need to improve the efficiency of phase 2 clinical testing in neuro-oncology to expeditiously transition the most promising of these drugs or combinations to potentially practice-changing phase 3 trials. In this report from the Response Assessment in Neurooncology (RANO) group, we review phase 2 trial designs that can address these challenges and capitalise on scientific and clinical advances in brain tumour treatment in neuro-oncology to accelerate and optimise the selection of drugs deserving further testing in phase 3 trials. Although there is still a small role for single-arm and non-comparative phase 2 designs, emphasis is placed on the potential role that comparative randomised phase 2 designs—such as screening designs, selection designs, discontinuation designs, and adaptive designs, including seamless phase 2/3 designs—can have. The rational incorporation of these designs, as determined by the specific clinical setting and the trial''s endpoints or goals, has the potential to substantially advance new drug development in neuro-oncology. [Copyright &y& Elsevier]
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- 2012
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