Silent Diffuse Low-Grade Glioma: Toward Screening and Preventive Treatment?

Transcription

1 Silent Diffuse Low- Glioma: Toward Screening and Preventive Treatment? Emmanuel Mandonnet, MD, PhD 1,2,3 ; Philip de Witt Hamer, MD, PhD 4 ; Johan Pallud, MD, PhD 5,6 ; Luc Bauchet, MD, PhD 7 ; Ian Whittle, MD, PhD 8 ; and Hugues Duffau, MD, PhD 7,9 INTRODUCTION Diffuse low-grade glioma (DLGG) is a progressive primary brain tumor for which several stages can be discerned (see Fig. 1). First, glioma-initiating cells neoplastically transform, which we define as the biologic birth. This nascent glioma does not give rise to any symptoms and even remains below the detection limit of routine magnetic resonance imaging (MRI), during what we term the occult stage. Second, at some point, the glioma becomes visible on MRI, yet the patient is still asymptomatic; we refer to this as the clinically silent stage. During this stage, gliomas can be incidentally discovered on brain MRI, for instance, in healthy volunteers from a study, in trauma patients requiring brain imaging, or in clients of commercial screening programs. Third, the glioma elicits clinical symptoms, usually an epileptic seizure, entering what we define as its symptomatic stage. Fourth, at some point in time, the glioma switches its rather indolent behavior toward an aggressive one, in keeping with the onset of neoangiogenesis and malignancy, until the patient dies from tumor spread and growth. To date, oncologic therapy has failed to cure patients with DLGG, but a significant delay of malignant transformation and death from disease can be achieved by appropriate and timely treatment. 1 The treatment modalities include surgical resection, chemotherapy, and radiotherapy. Considerable debate has focused on the optimal timing of each treatment modality. 2 Despite the lack of evidence from randomized surgical trials, expert opinion 3 based on accumulating evidence from observational studies favors early resective surgery for symptomatic DLGG because of both a substantial survival benefit and low morbidity. 4-6 Currently, patients with DLGG are almost always diagnosed in their symptomatic period. However, given the increasing availability of MRI and more liberal brain imaging indications, incidental discoveries of a silent DLGG are becoming more frequent. The management of these patients has been discussed in several recent publications In particular, early surgery has been advocated, arguing that the sooner the surgery, the higher the chances to perform a (supra)- complete, 13 functionally safe 7,14 resection guided by the use of intraoperative brain-stimulation mapping. The idea that the early detection of silent DLGG could contribute to a cure for these tumors even led some authors to propose a screening policy. 15 However, before setting up a population screening, with the objective of offering immediate treatment to any patient diagnosed with a silent DLGG, at least 2 fundamental questions, among many others, remain to be answered. First, what is the risk over a lifetime of dying with a silent glioma from another cause compared with the risk of dying from the evolution of the silent glioma? In other words, is there a risk of overtreatment? Second, how long is the silent stage of a DLGG; or, stated differently, what is the average lead time? In this commentary, we address these 2 questions based on epidemiologic computations and biomathematical models of glioma growth, and we address the issue of a screening policy. Corresponding author: Emmanuel Mandonnet, MD, Department of Neurosurgery, Lariboisiere Hospital, 2 rue Ambroise Pare, Paris, France; Fax: ( ); mandonnet@mac.com 1 Department of Neurosurgery, Lariboisiere Hospital, Paris, France; 2 University of Paris 7, Paris, France; 3 Imaging and Modeling Laboratory for Neurobiology and Oncology, Medical Research Unit 8165, Orsay, France; 4 Department of Neurosurgery, VU University Medical Center, Amsterdam, the Netherlands; 5 Department of Neurosurgery, Saint-Anne Hospital, Paris, France; 6 University of Paris 5, Paris, France; 7 Department of Neurosurgery, Gui de Chauliac Hospital, Montpellier Medical University Center, Montpellier, France; 8 Department of Clinical Neurosciences, University of Edinburgh, Edinburgh, United Kingdom; 9 Institute of Health and Medical Research Unit 1051, Institute of Neuroscience of Montpellier, Montpellier, France DOI: /cncr.28610, Received: September 16, 2013; Revised: November 16, 2013; Accepted: December 12, 2013, Published online March 11, 2014 in Wiley Online Library (wileyonlinelibrary.com) 1758 Cancer June 15, 2014

2 Screening and Treating Silent DLGG/Mandonnet et al Figure 1. The schematic natural history of a diffuse low-grade glioma (DLGG) is illustrated. After biologic birth, the DLGG remains occult on magnetic resonance imaging until its radiologic birth; then, it enters the (clinically) silent stage. A patient with a silent DLGG can die from another cause (annual incidence i 1 ) or can become symptomatic as a grade II, III or IV (respective incidences of i 2, i 3, and i 4 ) and ultimately die from the glioma. Assuming a stable prevalence p of silent DLGG, their incidence is calculated as i 5 i 1 1 i 2 1 i 3 1 i 4. The lead time is the average duration of the silent phase. It can be estimated as p/i. Comparing the 2 Risks of Dying With Versus From a Silent DLGG The natural history of a silent DLGG is poorly known. Not surprisingly, it has been reported that, at some point, a patient with silent DLGG can become the typical epileptic grade II patient. 9,10 Thus, a DLGG can turn out to be symptomatic while it is still a grade II tumor. Alternatively and somehow unexpectedly, DLGG may remain clinically silent until malignant transformation, thus entering the symptomatic phase directly as a grade III or IV glioma. 16 Hence, the fate of a patient with silent DLGG is 1 of the following exclusive events (see Fig. 1): 1) death from another cause, 2) the tumor becomes symptomatic as a DLGG (grade II), 3) the tumor becomes symptomatic as a secondary anaplastic glioma (grade III), and 4) the tumor becomes symptomatic as a secondary glioblastoma (grade IV). The yearly incidence i 1 of event 1 is equal to m 3 p, where m is the overall mortality (750 per 100,000 per year in France 17 ), and p is the prevalence of silent DLGG. The exact value of the prevalence p is unknown, but it has been estimated at approximately 0.04% (range, 0.02%-0.09%) based on a meta-analysis of brain MRI studies in healthy populations. 18 The incidence i 2 of event 2 is approximately 1 per 100,000 per year. 19 To compute the incidences of events 3 and 4, we assume here that the presence of an isocitrate dehydrogenase 1 (IDH1)/IDH2 mutation identifies these secondary grade III and IV gliomas that evolved from silent DLGGs. The finding that grade III and IV gliomas with IDH1/IDH2 mutations are preferentially located in the frontal lobes 20,21 provides an indirect argument supporting this hypothesis: because of the low epileptogenicity of the frontal lobes and the slight symptoms associated with frontal lobe dysfunction, it does not come as a surprise that these lesions may remain silent during their grade II stage, coming out later in time, after malignant transformation. Considering that 55% of grade III gliomas and 6% of grade IV gliomas harbor an IDH1/IDH2 mutation, 22 the incidences are estimated as i per 100,000 per year for event 3 and i per per year for event Let us use d n (x) to denote the proportion of patients who die within x years after diagnosis of symptomatic glioma of grade n. This rate is deduced from the Kaplan- Meier curves for the considered glioma of grade n. We want to compare the number of individuals who have silent glioma and die from another cause over a period of N years (deaths from another cause [DAC]) versus the number who die during the same period of N years from a silent glioma that would have turned out to be symptomatic in the meantime (deaths from silent glioma [DSG]). Because we assume that p and m are constant over time, the first quantity is simply DAC 5 i 1 3 N. The second quantity is given by DSG 5 R DSG n, where DSG n 5 i n 3 d n( 1) 1 i n 3 d n (2) i n 3 d n (N). Hence, 3 terms have to be computed in our case: DSG 5 DSG 2 1 DSG 3 1 DSG 4, corresponding to deaths arising from a silent glioma that would have transformed, respectively, to a symptomatic grade II, III, and IV Cancer June 15,

3 TABLE 1. Statistical Calculations a Mortality Rate per 100,000 Inhabitants Year II III IV Mortality From Glioma Cumulated Mortality From Glioma Figure 2. Cumulative death rates are illustrated. The blue curve represents the cumulative deaths from another cause with a silent glioma (expressed per 100,000 inhabitants), and the red curve represents the cumulative deaths from the evolving silent glioma (expressed per 100,000 inhabitants). glioma. To compute DSG 2, we estimated d 2 (x) from a large series of symptomatic grade II gliomas. 4 Similarly, d 3 (x) and d 4 (x) were estimated from a recent publication. 22 Table 1 details the computation of DSG(N) and figure 2 provides the curves DAC(N) and DSG(N). We conclude that the 2 curves cross at approximately N 5 4 years. Above this value, DSG(N) outweighs DAC(N). In summary, when a silent glioma is incidentally diagnosed, there are more chances of dying from the evolution of the silent glioma toward a symptomatic glioma than dying from another cause with the glioma (which would have remained silent), unless patient survival is expected to be <4 years. In keeping with this result, we observed that silent gliomas are discovered very rarely in autopsy series. According to a review of the literature, only 1 silent DLGG was detected with no relation to death in 112,333 autopsies, resulting in an estimated silent DLGG prevalence of 0.89 in 100,000 deaths from another cause. Although this cannot be considered definite proof, given the difficulty of diagnosing small silent DLGGs at autopsy, such a low value compared with the 4 in 10,000 prevalence of silent DLGG reinforces the idea that most patients who have silent DLGG ultimately will die from their glioma. Silent DLGG: A Multiyear Phase Assuming that p remains constant over a 1-year period, the incidence of silent DLGG is given by i 5 i 1 1 i 2 1 i 3 1 i 4, where i 1 through i 4 are the incidences of events 1 through 4. The average duration of the a The mortality rates of grade II glioma, isocitrate dehydrogenase (IDH)- mutated grade III glioma, and IDH-mutated grade IV glioma are estimated from survival curves in the literature. The fourth column is the sum of the 3 previous columns, weighted by the respective incidences of these events: 1 3 column column column 3. The fifth column is the cumulated sum, that is, the total number of deaths from silent glioma. silent stage is then obtained by Dt 5 p/i. For p 5.04%, the result is Dt years. A quite similar lead-time value can be obtained using a completely different approach. The diameter of symptomatic, untreated DLGGs grow linearly in time, on average 4 mm per year (range, 1-8 mm per year) If an identical growth rate is assumed between symptomatic and silent DLGGs, then the duration of the silent stage can be estimated from the initial DLGG size and its growth rate (Dt 5 D i /VDE, where D i denotes the initial tumor diameter on MRI, and VDE denotes the velocity of diameter expansion based on subsequent MRIs). Averaging this formula over a large series of 148 patients with a VDE <8 mm per year yields Dt 5 14 years. 30 These results give full support to the intuition of Kelly 15 that, currently, symptomatic DLGGs are diagnosed too late to be surgically cured: during the silent stage, glioma cells invade the brain (beyond the margins observed on MRI 31 ), precluding the removal of every single glioma cell. Moreover, it can be anticipated that, during this long silent evolution, DLGGs will increase their genomic heterogeneity, contributing to the development of the chemoresistance of these tumors. Toward a Screening Policy and Preventive Surgery for Silent DLGG Despite the lack of class I evidence, it is widely accepted that the extent of surgical resection contributes to improve outcomes of DLGG, 4-6 and surgery is currently the recommended standard for first-line treatment. 3 Concomitantly, the consequences of extensive resection on the quality of life of patients are now much better 1760 Cancer June 15, 2014

4 Screening and Treating Silent DLGG/Mandonnet et al controlled, 14 thanks to preoperative and intraoperative techniques of brain function mapping. Thus, as recently demonstrated in a small retrospective series, 13 the oncologic benefit of surgery is expected to be even greater after supracomplete resection (ie, removing a rim of radiologically normal but microscopically infiltrated tissue) while still preserving functional networks along with the patient s cognitive abilities and quality of life. 7 Integrating these clinical data about the efficacy of supracomplete resections with the aforementioned results leads to the following statements: Preventive treatment of DLGGs discovered incidentally in their silent phase is warranted, because there are more chances of dying from the transformation of the silent glioma into a symptomatic glioma than dying from another cause with the silent glioma; Screening by systematic MRI is feasible, because the window of opportunity to detect a DLGG in its silent period is quite large (approximately 15 years); and Early treatment of screened, silent DLGG is expected to be more effective: the sooner we can detect a silent glioma, the smaller its visible and nonvisible extent, and the greater the chances of performing a supracomplete resection with a minimal functional risk. In addition, we would expect enhanced chemosensitivity compared with symptomatic DLGG, thanks to lower genomic heterogeneity. Of course, several other issues should be addressed before a screening project is launched, including the sensitivity and specificity of MRI for detecting silent DLGG and the management of all incidentally discovered lesions other than DLGG. Moreover, as stated by Kelly, the costeffectiveness of this strategy is not clear-cut. A thorough cost-effectiveness analysis would be beyond the scope of this commentary, but preliminary estimates warrant further sophisticated computations. Indeed, if we assume that the cost of a screening MRI (ie, a single fluid-attenuated inversion recovery [FLAIR] sequence) is approximately $150 in US dollars, then the screening of 10,000 individuals will cost $1,500,000; and, among those screened, 4 will have a silent DLGG detected. Economists estimate that the value of 1 person-year is $120,000. This means that the costeffectiveness ratio will be >1 if at least 3 years of life can be saved by early treatment. Moreover, we can reasonably anticipate that epidemiologic advances (including biomathematical models to determine the optimal class age to be targeted) 32 and the availability of new biomarkers of glioma risk will enable the screening to focus on specific subpopulations, hence greatly reducing the cost. Last but not least, the finding that this strategy has proven to be successful in other fields of oncology 33,34 should definitely encourage the neuro-oncologic community to envision a screening policy for DLGG. FUNDING SUPPORT No specific funding was disclosed. CONFLICT OF INTEREST DISCLOSURES The authors made no disclosures. REFERENCES 1. Youland RS, Schomas DA, Brown PD, et al. Changes in presentation, treatment, and outcomes of adult low-grade gliomas over the past fifty years. Neuro Oncol. 2013;15: Whittle IR. What is the place of conservative management for adult supratentorial low-grade glioma? Adv Tech Stand Neurosurg. 2010; 35: Soffietti R, Baumert BG, Bello L, et al. European Federation of Neurological Societies. Guidelines on management of low-grade gliomas: report of an EFNS-EANO Task Force. Eur J Neurol. 2010;17: Capelle L, Fontaine D, Mandonnet E, et al. Spontaneous and therapeutic prognostic factors in adult hemispheric World Health Organization grade II gliomas: a series of 1097 cases. J Neurosurg. 2013; 118: Jakola AS, Myrmel KS, Kloster R, et al. Comparison of a strategy favoring early surgical resection vs a strategy favoring watchful waiting in low-grade gliomas. JAMA. 2012;308: Smith JS, Chang EF, Lamborn KR, et al. Role of extent of resection in the long-term outcome of low-grade hemispheric gliomas. J Clin Oncol. 2008;26: Duffau H. Awake surgery for incidental WHO grade II gliomas involving eloquent areas. Acta Neurochir (Wien) 154: , 2011; discussion Duffau H. The rationale to perform early resection in incidental diffuse low-grade glioma: toward a preventive surgical neurooncology [serial online]. World Neurosurg. 2013;80:e115-e Pallud J, Fontaine D, Duffau H, et al. Natural history of incidental World Health Organization grade II gliomas. Ann Neurol. 2010;68: Potts MB, Smith JS, Molinaro AM, Berger MS. Natural history and surgical management of incidentally discovered low-grade gliomas. J Neurosurg. 2012;116: Shah AH, Madhavan K, Heros D, et al. The management of incidental low-grade gliomas using magnetic resonance imaging: systematic review and optimal treatment paradigm [serial online]. Neurosurg Focus. 2011;31:E Shah AH, Madhavan K, Sastry A, Komotar RJ. Managing intracranial incidental findings suggestive of low-grade glioma: learning from experience [serial online]. World Neurosurg. 2013;80:e75-e Yordanova YN, Moritz-Gasser S, Duffau H. Awake surgery for WHO grade II gliomas within noneloquent areas in the left dominant hemisphere: toward a supratotal resection. Clinical article. J Neurosurg. 2011;115: de Witt Hamer PC, Robles SG, Zwinderman AH, Duffau H, Berger MS. Impact of intraoperative stimulation brain mapping on glioma surgery outcome: a meta-analysis. J Clin Oncol. 2012;30: Kelly PJ. Gliomas: survival, origin and early detection [serial online]. Surg Neurol Int. 2010;1: Floeth FW, Sabel M, Stoffels G, et al. Prognostic value of 18Ffluoroethyl-L-tyrosine PET and MRI in small nonspecific incidental brain lesions. J Nucl Med. 2008;49: National Institute of Statistics and Economic Studies (INSEE). INSEE database, Available at: Cancer June 15,

5 donnees/bsweb/serie.asp?idbank Accessed on September 1, Morris Z, Whiteley WN, Longstreth WT Jr, et al. Incidental findings on brain magnetic resonance imaging: systematic review and meta-analysis [serial online]. BMJ. 2009;339:b Zouaoui S, Rigau V, Mathieu-Daude H, et al. [French brain tumor database: general results on 40,000 cases, main current applications and future prospects]. Neurochirurgie. 2012;58: Yan W, Zhang W, You G, et al. Correlation of IDH1 mutation with clinicopathologic factors and prognosis in primary glioblastoma: a report of 118 patients from China [serial online]. PLoS One. 2012; 7:e Zhang CB, Bao ZS, Wang HJ, et al. Correlation of IDH1/2 mutation with clinicopathologic factors and prognosis in anaplastic gliomas: a report of 203 patients from China. J Cancer Res Clin Oncol. 2014;140: Sanson M, Marie Y, Paris S, et al. Isocitrate dehydrogenase 1 codon 132 mutation is an important prognostic biomarker in gliomas. J Clin Oncol. 2009;27: Cooney LM Jr, Solitare GB. Primary intracranial tumors in the elderly. Geriatrics. 1972;27: DiMaio SM, DiMaio VJ, Kirkpatrick JB. Sudden, unexpected deaths due to primary intracranial neoplasms. Am J Forensic Med Pathol. 1980;1: Eberhart CG, Morrison A, Gyure KA, Frazier J, Smialek JE, Troncoso JC. Decreasing incidence of sudden death due to undiagnosed primary central nervous system tumors. Arch Pathol Lab Med. 2001;125: Gezelius C, Eriksson A. Neoplastic disease in a medicolegal autopsy material. A retrospective study in northern Sweden. Z Rechtsmed. 1988;101: Mandonnet E, Delattre JY, Tanguy ML, et al. Continuous growth of mean tumor diameter in a subset of grade II gliomas. Ann Neurol. 2003;53: Pallud J, Mandonnet E, Duffau H, et al. Prognostic value of initial magnetic resonance imaging growth rates for World Health Organization grade II gliomas. Ann Neurol. 2006;60: Pallud J, Taillandier L, Capelle L, et al. Quantitative morphological magnetic resonance imaging follow-up of low-grade glioma: a plea for systematic measurement of growth rates. Neurosurgery. 2012;71: Pallud J, Capelle L, Taillandier L, Duffau H, Mandonnet E. The silent phase of diffuse low-grade gliomas. Is it when we missed the action? Acta Neurochir (Wien). 2013;155: Pallud J, Varlet P, Devaux B, et al. Diffuse low-grade oligodendrogliomas extend beyond MRI-defined abnormalities. Neurology. 2010; 74: Gerin C, Pallud J, Grammaticos B, et al. Improving the timemachine: estimating date of birth of grade II gliomas. Cell Prolif. 2011;45: Independent UK Panel on Breast Cancer Screening. The benefits and harms of breast cancer screening: an independent review. Lancet. 2012;380: Aberle DR, Adams AM, Berg CD, et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med. 2011;365: Cancer June 15, 2014