Functional outcome measures for NF1-associated optic pathway glioma clinical trials

Fisher, Michael J.; Avery, Robert A.; Allen, Jeffrey C.; Ardern‐Holmes, Simone; Bilaniuk, Larissa T.; Ferner, Rosalie E.; Gutmann, David H.; Listernick, Robert; Martin, Staci; Ullrich, Nicole J.; Liu, Grant T.

doi:10.1212/01.wnl.0000435745.95155.b8

Cited by 108 publications

(106 citation statements)

References 57 publications

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“…Guidelines for management of NF1 have been published by several different professional organizations and concentrate on the diagnosis and management of OPG (48)(49)(50)(51).…”

Section: Malignancies In Nf1mentioning

confidence: 99%

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Cancer and Central Nervous System Tumor Surveillance in Pediatric Neurofibromatosis 1

Evans

Salvador

Chang

et al. 2017

Clinical Cancer Research

148

120

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Although the neurofibromatoses consist of at least three autosomal dominantly inherited disorders, neurofibromatosis 1 (NF1), neurofibromatosis 2 (NF2), and schwannomatosis, NF1 represents a multisystem pleiotropic condition very different from the other two. NF1 is a genetic syndrome first manifesting in childhood; affecting multiple organs, childhood development, and neurocognitive status; and presenting the clinician with often complex management decisions that require a multidisciplinary approach. Molecular genetic testing (see article for detailed discussion) is recommended to confirm NF1, particularly in children fulfilling only pigmentary features of the diagnostic criteria. Although cancer risk is not the major issue facing an individual with NF1 during childhood, the condition causes significantly increased malignancy risks compared with the general population. Specifically, NF1 is associated with highly elevated risks of juvenile myelomonocytic leukemia, rhabdomyosarcoma, and malignant peripheral nerve sheath tumor as well as substantial risks of noninvasive pilocytic astrocytoma, particularly optic pathway glioma (OPG), which represent a major management issue. Until 8 years of age, clinical assessment for OPG is advised every 6 to 12 months, but routine MRI assessment is not currently advised in asymptomatic individuals with NF1 and no signs of clinical visual pathway disturbance. Routine surveillance for other malignancies is not recommended, but clinicians and parents should be aware of the small risks (<1%) of certain specific individual malignancies (e.g., rhabdomyosarcoma). Tumors do contribute to both morbidity and mortality, especially later in life. A single whole-body MRI should be considered at transition to adulthood to assist in determining approaches to long-term follow-up. Clin Cancer Res; 23(12); e46–e53. ©2017 AACR. See all articles in the online-only CCR Pediatric Oncology Series.

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“…Guidelines for management of NF1 have been published by several different professional organizations and concentrate on the diagnosis and management of OPG (48)(49)(50)(51).…”

Section: Malignancies In Nf1mentioning

confidence: 99%

“…65). In older children (usually at developmental age of 3 years), testing methods measure the ability to recognize ("recognition acuity") a figure (e.g., Lea symbols) or letters (e.g., HOTV or Snellen).…”

Section: Genetic Testing Recommendationsmentioning

confidence: 99%

Cancer and Central Nervous System Tumor Surveillance in Pediatric Neurofibromatosis 1

Evans

Salvador

Chang

et al. 2017

Clinical Cancer Research

148

120

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“…A description of the REiNS International Collaboration and its 7 working groups and initial recommendations of 4 working groups were published previously in Neurology. [5][6][7][8][9][10] In brief, the imaging working group provided recommendations for the use of MRI with volumetric analysis to evaluate response in clinical trials targeting histologically benign nerve sheath tumors such as plexiform neurofibromas and vestibular schwannomas. 5 The patientreported outcomes (PRO) working group described their approach for the objective selection of PRO measures in NF trials, and they recommended the use of Numeric Rating Scale-11 (NRS-11) as a measure of pain intensity for manifestations associated with pain.…”

mentioning

confidence: 99%

“…10 The visual outcomes working group recommended the use of visual acuity as primary endpoint in clinical trials for optic pathway gliomas as opposed to measurement of tumor size. 6 Finally, the functional outcomes working group provided recommendations for hearing response measured by word recognition as primary endpoint in trials for NF2-related vestibular schwannomas. 7 Since the publication of these recommendations in 2013, a number of ongoing clinical trials have incorporated these outcome measures.…”

mentioning

confidence: 99%

Consensus for NF clinical trials

Widemann

Plotkin

2016

Neurology

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The neurofibromatoses (NFs) can result in substantial morbidity in affected patients. In order to accelerate the development of effective therapies for NF-related tumor and nontumor manifestations, the development of standardized meaningful outcome measures for clinical trials is critical. The Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) International Collaboration was established with the goal to develop consensus recommendations for outcome measures and endpoints in future NF trials and provided the first set of recommendations in a Neurology ® supplement in 2013. This second supplement updates on clinical trials that have incorporated the recommended measures and provides new recommendations for (1) standardized and specific cognitive assessment tools for use in NF clinical trials, (2) patient-reported outcome measures including pain and physical functioning, (3) functional outcome measures for airway plexiform neurofibromas, (4) the use of whole-body MRI in NF, and (5) the development of biomarkers in NF and guidelines for collection of biospecimens and establishment of biobanks for neurofibromatosis 1 (NF1), neurofibromatosis 2 (NF2), and schwannomatosis. Through engagement of the NF research community, regulatory agencies, NF advocacy groups, industry, and patients with NF, REiNS will provide a framework for comprehensive review of these recommendations, continue development of outcome measures relevant to patients, and compare results of trials, which use identical outcome measures. Neurology ® 2016;87 (Suppl 1):S1-S3 GLOSSARY NF 5 neurofibromatosis; NF1 5 neurofibromatosis 1; NF2 5 neurofibromatosis 2; NRS-11 5 Numeric Rating Scale-11; PRO 5 patient-reported outcomes; REiNS 5 Response Evaluation in Neurofibromatosis and Schwannomatosis.The NFs-including NF1, NF2, and schwannomatosis-are genetic tumor-predisposition syndromes characterized by the development of multiple tumor manifestations, in particular nerve sheath tumors, for most of which no standard treatment options other than surgery exist. [1][2][3] In addition, patients with NF can develop multiple nontumor manifestations, affecting many organ systems, which can result in substantial morbidity and reduced quality of life. There is an unmet need for effective medical therapies for NF-related manifestations. Differences between NF-related tumors and nonsyndromic solid cancers have limited the applicability of clinical trial designs used in oncology trials to the development of trials for NF. 4 The REiNS International Collaboration was established in 2011 with the primary goal to achieve consensus within the NF community for outcome measures and endpoints for future NF trials. A description of the REiNS International Collaboration and its 7 working groups and initial recommendations of 4 working groups were published previously in Neurology. 5-10In brief, the imaging working group provided recommendations for the use of MRI with volumetric analysis to evaluate response in clinical trials targeting histologically beni...

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“…In addition, following NF1-OPG identification, there are no reliable methods for determining which child is most likely to experience continued visual decline and require treatment, necessitating frequent MRI (often requiring sedation) and neuro-ophthalmologic evaluations, which can be unreliable in preverbal children. 25,26 At present, affected children typically receive chemotherapy routinely used for sporadic PA (carboplatin/vincristine), with varying success. Radiation therapy is not used because of the elevated risk of secondary cancer development in this cancer predisposition syndrome.…”

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confidence: 99%

Eliminating barriers to personalized medicine

Gutmann

2014

Neurology

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With the emergence of high-throughput discovery platforms, robust preclinical small-animal models, and efficient clinical trial pipelines, it is becoming possible to envision a time when the treatment of human neurologic diseases will become personalized. The emergence of precision medicine will require the identification of subgroups of patients most likely to respond to specific biologically based therapies. This stratification only becomes possible when the determinants that contribute to disease heterogeneity become more fully elucidated. This review discusses the defining factors that underlie disease heterogeneity relevant to the potential for individualized brain tumor (optic pathway glioma) treatments arising in the common single-gene cancer predisposition syndrome, neurofibromatosis type 1 (NF1). In this regard, NF1 is posited as a model genetic condition to establish a workable paradigm for actualizing precision therapeutics for other neurologic disorders. Neurology ® 2014;83:463-471 GLOSSARY cAMP 5 cyclic adenosine monophosphate; GEM 5 genetically engineered mouse; GWAS 5 genome-wide association studies; mTOR 5 mammalian target of rapamycin; NF1 5 neurofibromatosis type 1; NSC 5 neural stem cell; OPG 5 optic pathway glioma; PA 5 pilocytic astrocytoma; RGC 5 retinal ganglion cell.Neurofibromatosis type 1 (NF1) is one of the most common monogenic disorders in which affected individuals develop benign and malignant tumors.1 NF1 impacts 1:2,500 people worldwide, and individuals with NF1 are prone to the development of peripheral (neurofibromas, malignant peripheral nerve sheath tumors) and central (optic pathway glioma, malignant glioma) nervous system tumors.2,3 Similar to other autosomal dominant cancer predisposition syndromes, 4,5 people with NF1 start life with a germline mutation in one copy of the NF1 tumor suppressor gene; however, tumors require somatic (acquired) inactivation of the remaining functional NF1 allele, leading to complete loss of NF1 expression in specific cell types.6,7 For example, complete Nf1 gene inactivation in neuroglial 8,9 or Schwann cell 10,11 progenitors is required for murine optic glioma or neurofibroma formation, respectively.With the development of numerous accurate small-animal (genetically engineered mouse; GEM) models of NF1-associated nervous system tumors ( the stage has been set for the discovery and validation of promising therapeutic strategies and their translation to people affected with NF1. However, despite these advances, there are currently no effective therapies, which likely reflects the striking biological and clinical heterogeneity inherent to this condition. This review uses NF1-associated brain tumors (optic glioma) as an illustrative platform to discuss the barriers and challenges to developing and implementing effective targeted therapies.NF1-ASSOCIATED OPTIC PATHWAY GLIOMA NF1-associated optic pathway gliomas (NF1-OPGs) are largely pediatric tumors typically arising in children younger than 7 years of age. 21,22 As such, 15%-20% of child...

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Functional outcome measures for NF1-associated optic pathway glioma clinical trials

Cited by 108 publications

References 57 publications

Cancer and Central Nervous System Tumor Surveillance in Pediatric Neurofibromatosis 1

Cancer and Central Nervous System Tumor Surveillance in Pediatric Neurofibromatosis 1

Consensus for NF clinical trials

Eliminating barriers to personalized medicine

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