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AANS Neurosurgeon | Volume 28, Number 3, 2019

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Neuro-Oncology Timeline

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Editor’s Note: One obvious way to think about the world of neurosurgery is that it is the culmination of all the care delivered across the subspecialties. Just a few decades ago, subspecialization (and the whole world of CAST, enfolded fellowships, post-residency fellowships, etc.) was the exception, limited to just a small number of academics. Today it plays a much larger role across the neurosurgical spectrum. In a series of pieces, AANS Neurosurgeon explores each of the subspecialties in neurosurgery’s orbit. 

The care of patients with central nervous system (CNS) tumors remains a challenging and complex undertaking, marked by frequent “promising” breakthroughs, but few that ultimately impact clinical management. The growing sophistication of diagnostic tests, chemotherapeutics and adjuvant medical management requires constant vigilance to an ever-increasing body of knowledge, with appropriate adaptation to each patient’s unique history and goals of care. The formalized field of neuro-oncology initially grew from collaborations between neurosurgeons, neurologists and oncologists, who recognized the need for dedicated teams to manage increasingly complex therapeutic regimens in medically challenging patients. Since the first brain tumor research meeting held in Asilomar in 1975, interest in the field of neuro-oncology has grown exponentially. Dedicated fellowships were developed in the 1980s, and a number of national societies were subsequently inaugurated, including the Japanese Society for Neuro-Oncology (1980), Korean Society for Neuro-Oncology (1991), European Association of Neuro-Oncology (1994) and the (American) Society of Neuro-Oncology (1996). Subsequently, these societies have provided an invaluable platform for dissemination of ideas, promotion of education and advancement of scientific research.

Progress in clinical neuro-oncology depends on a perpetual cycle of scientific discovery, clinical translation and pilot protocols, randomized trials (with either rejection or confirmation of the hypothesis) and treatment optimization in both the laboratory and the bedside – a process that can take a decade or more. Surgical excision remains the mainstay of treatment for most CNS neoplasms, with abundant, albeit non-randomized, evidence supporting its role. After controlling for other prognostic factors, early surgical resection results in better survival than watchful waiting in low-grade glioma1, and numerous studies have correlated extent of resection and long-term survival in both low and high grade glioma.2-4 In addition to therapeutic benefit, surgical excision provides tissue for pathologic studies, which is essential for selection of appropriate adjuvant therapies. Advancements in neurosurgical oncology have focused on optimizing extent of resection and include the ubiquitous adaptation of the operating microscope, the development of image-guided surgery and the use of intra-tumoral florescence using 5-aminolevulinic acid.5 Indeed, recent work continues to validate the role of extent of resection in the molecular age, with increased survival shown in maximally resected glioblastoma independent of IDH1 status.6 However, disagreement can exist among experts about the resectability of a given lesion7, and even complete resection is rarely curative.8

Seminal studies in neuro-oncology have transformed approaches to management and prognostication (Figure 1). For example, the use of adjuvant radiotherapy has become standard of care for most malignant lesions, following early studies that demonstrated benefit in high-grade gliomas.9 Considerable attention has also focused on the role of chemotherapy in CNS tumors, with numerous cytotoxic drugs and combinations being investigated and aiming to replicate the successes observed in medical oncology. Anaplastic oligodendrogliomas were among the first to be identified as truly chemo-sensitive tumors, exhibiting a durable response to combination therapy of procarbazine, lomustine and vincristine (PCV)10-11 or adjuvant carmustine.12 They are also responsive to radiation therapy and have a more protracted natural history irrespective of the treatment modality. Subsequently, the biology of oligodendroglioma has been associated with loss of chromosomes 1p and 19q (later identified as a translocation)13-14, and this genomic feature has become pathognomonic for these tumors.

Figure 1: Listed are a selection of seminal events that impacted the field of glioma treatment during the past 45 years. BTSG: Brain Tumor Study Group, RT: Radiation Therapy, ECOG: Eastern Cooperative Oncology Group, PCV: Procarbazine, Lomustine, and Vincristine, RTOG: Radiation Therapy Oncology Group, LOH: Loss of Heterozygosity, TMZ: Temozolomide, CPT11: Irinotecan, DFMO: DiFluoroMethylOrnithine, ANCU: Nimustine, MGMT: Methylated O6-MethylGuanine-DNA MethylTransferase, EGFR: Epidermal Growth Factor Receptor, VEGF: Vascular Endothelial Growth Factor

Glioblastoma, the most common and deadly adult primary brain tumor, has been the subject of extensive research, though clinical outcomes remain overall dismal. Contemporary standard of care includes maximal surgical resection, followed by adjuvant radiation with concomitant and maintenance temozolomide (TMZ) chemotherapy.15-16 This strategy increased the two-year survival rate from 10% to 27%, though only 10% of patients remained alive after five years (compared to 3% who did not receive chemotherapy as part of the initial management).15 Notably, patient response to TMZ depends upon promoter methylation of the DNA repair gene O6-methylguanine–DNA methyltransferase17 (resulting in epigenetic inactivation). This predictive marker is now part of routine pathological assessment, allowing for better prognostication and individualization of the post-operative treatment strategy. Recent work has also investigated the use of concomitant tumor treating fields (TTFields), a novel treatment modality thought to disrupt cell division and organelle assembly. A large phase III trial demonstrated improved progression-free and overall survival when TTFields were added to standard maintenance TMZ chemotherapy early in the disease course.18-20

The notable progress made over the past four decades has not come without setbacks, with “promising” results from pre-clinical or phase I/II trials often failing to show efficacy in subsequent phase III trials. Prominent examples in glioblastoma include targeting VEGFR and VEGF by cediranib21-22 or bevacizumab23-24, Cilengitide25-26, as well as Rindopepimut and other EGFR inhibitors.27-28 A persistent challenge in the treatment of CNS tumors is the presence of a blood-brain barrier, which can reduce penetrance of drug therapy and thereby decrease efficacy. Recent work has investigated blood-brain barrier disruption using a variety of techniques, including radiation, ultrasound or osmotic agents29 and ongoing trials in humans will ultimately determine the utility of these approaches.30 The employment of surgery for localized delivery of chemotherapeutics has also shown promise, for example the intraoperative implantation of biodegradable carmustine (Gliadel) wafers.31 However, both concentration and extent of diffusion were insufficient to allow for a sustained antitumor effect. Current investigations are using oncolytic virus injection during surgical resection to improve regional control, change the immunological milieu and microenvironment or deliver cytotoxic agents, though preliminary analyses provide inconsistent results.32-35

As our understanding of tumor pathogenesis and progression continues to mature, clinical neuro-oncology has become an increasingly precise enterprise. Early studies on chemotherapeutics focused on large heterogeneous cohorts, segregated primarily by histological attributes such as putative cell of origin or presence of aggressive features. The advent and proliferation of molecular profiling has led to increasing disease stratification, with the goal of tailoring chemotherapeutics and specific genomic or epigenetic signatures. This new dimension of tumor profiling has also increased the accuracy of prognosis, facilitating optimal clinical management and expectation setting. Continued development of precision treatments, methods of earlier detection and diagnosis, along with finding an optimal balance between surgical and medical approaches, will further improve outcomes among patients with CNS tumors and likely serve as the foundation for future management of these patients.

References

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15. Stupp, R., Hegi, M. E., Mason, W. P., Bent, M. J. V. D., Taphoorn, M. J., Janzer, R. C., … Mirimanoff, R.-O. (2009). Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. The Lancet Oncology10(5), 459–466. doi: 10.1016/s1470-2045(09)70025-7

16. Stupp, R., Mason, W. P., Bent, M. J. V. D., Weller, M., Fisher, B., Taphoorn, M. J., … Mirimanoff, R. O. (2005). Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma. New England Journal of Medicine352(10), 987–996. doi: 10.1056/nejmoa043330

17. Hegi, M. E., Diserens, A.-C., Gorlia, T., Hamou, M.-F., Tribolet, N. D., Weller, M., … Stupp, R. (2005). MGMTGene Silencing and Benefit from Temozolomide in Glioblastoma. New England Journal of Medicine352(10), 997–1003. doi: 10.1056/nejmoa043331

18. Stupp, R., Taillibert, S., Kanner, A., Read, W., Steinberg, D. M., Lhermitte, B., … Ram, Z. (2017). Effect of Tumor-Treating Fields Plus Maintenance Temozolomide vs Maintenance Temozolomide Alone on Survival in Patients With Glioblastoma. Jama318(23), 2306–2316. doi: 10.1001/jama.2017.18718

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20. Stupp, R., Wong, E. T., Kanner, A. A., Steinberg, D., Engelhard, H., Heidecke, V., … Gutin, P. H. (2012). NovoTTF-100A versus physician’s choice chemotherapy in recurrent glioblastoma: A randomised phase III trial of a novel treatment modality. European Journal of Cancer48(14), 2192–2202. doi: 10.1016/j.ejca.2012.04.011

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32. Cloughesy, T. F., Mochizuki, A. Y., Orpilla, J. R., Hugo, W., Lee, A. H., Davidson, T. B., … Prins, R. M. (2019). Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma. Nature Medicine25(3), 477–486. doi: 10.1038/s41591-018-0337-7

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35. Reardon, D. A., Omuro, A., Brandes, A. A., Rieger, J., Wick, A., Sepulveda, J., … Sampson, J. (2017). OS10.3 Randomized Phase 3 Study Evaluating the Efficacy and Safety of Nivolumab vs Bevacizumab in Patients With Recurrent Glioblastoma: CheckMate 143. Neuro-Oncology19(suppl_3), iii21–iii21. doi: 10.1093/neuonc/nox036.071

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