Written by Masih Tazhibi:
Foreword: Diffuse Intrinsic Pontine Glioma (DIPG) is a pediatric, malignant brainstem tumor that is fatal. Past efforts in improving patient outcomes have been universally futile as this tumor has consistently evaded desperate efforts at therapy due to staunch physiological and bureaucratic complications. While such factors contributed to previous stagnation in the field, an array of promising therapeutic strategies are newly emerging. Nonetheless, even the most aggressive interventions currently offer only marginal survival benefit, are highly experimental, and rely on enrollment in extremely selective clinical trials with historically low racial and socioeconomic diversity. As such, in this paper I will first provide a comprehensive account of the pathogenesis, clinical presentation, and current standard of care for DIPG; next, I will highlight promising treatment avenues and their reliance on clinical trials; then, I will discuss the neurocognitive and family impacts associated with diagnosis and treatment of pediatric brain tumors; lastly, I will raise particularly potent questions about healthcare equity, the patient-physician relationship, and eliminating disparities in translational medicine.
DIPG & Current Standards
Childhood brain tumors are relatively widespread and represent approximately a quarter of all newly emerging cases (Hassan et al. 2017). Diffuse Intrinsic Pontine Glioma (DIPG), which consists of about 20% of all pediatric tumors of the central nervous system, is by far the most widely feared and lethal type of childhood brain tumor (Freeman et al. 1998). DIPGs originate in the pons from oligodendroglial progenitors and rapidly spread to adjacent brainstem and cerebellar areas, destroying in their path intricately arranged nuclei and cranial nerves critical for most essential homeostatic functions (Aziz-Bose & Monje 2019; Caretti et al. 2014; Monje et al. 2011; Qin et al. 2017). Over the course of tumor progression, patients present with balance and walking difficulties, vision problems, facial asymmetry, abducens palsy, obstructive hydrocephalus, and in later stages complete musculoskeletal paralysis (Matthew & Rutka 2018).
The current standard of care for most conventional low-grade gliomas of the central nervous system is to perform a craniotomy with three cardinal objectives: safely resect as much solid tumor tissue as possible, target chemotherapy-resistant cells, and limit intracranial swelling (Holland 2000). Surgical intervention is often followed by contrast-enhanced T1-weighted and fluid-attenuated inversion recovery (FLAIR) neuroimaging, as well as post-operative combination regimens with external beam radiotherapy and temozolomide chemotherapy, which sometimes, although not promisingly, lead to local tumor control (Gurwara et al. 2010; Holland 2000).
DIPG, however, completely evades the standard of therapy available today due to its unprecedented resistance to chemotherapy, its topographically dispersed and heterogeneous cellular expansion via the secondary structures of Scherer, and its general location in one of the most critical, yet delicate neural structures (Cohen et al. 2017; Jalali et al. 2010). Presently, radiotherapy in pediatric brainstem tumors is the sole treatment reliably demonstrating any clinical efficacy, and even the most aggressive administration regimes confer an average of only 3 months survival benefit (Aziz-Bose & Monje, 2019). As such, despite significant national attention to the etiology of DIPG and continuous research to improve patient outcomes, this tumor has time and time again circumvented increasingly innovative attempts at therapy over the last forty years. Today, it is still the foremost cause of tumor-associated mortality in children – with a median overall survival of 9-11 months and a two-year mortality rate of over 90% – evoking a sense of nihilism in the neurosurgery community with respect to the feasibility of treating these tumors (Freeman et al. 1998; Hargrave et al. 2006).
Advancing Therapies
Early research into the etiology and molecular profile of DIPG faced staunch bureaucratic resistance. A huge site of dispute was the ethicality, feasibility, and safety in conducting biopsies of brainstem tumors in DIPG patients (Puget et al. 2015; Cage et al. 2013). This was because although live tumor samples were required for histopathological analysis and research model development crucial to improving the dismal rates of DIPG survival, biopsy was thought to pose substantive risks with no direct quality-of-life improvements (Rashed et al. 2019). Over time, an increasing number of studies highlighted the safety and feasibility of tumor biopsy in DIPG patients and cited low rates of morbidity and mortality (Cage et al. 2013; Hamisch et al. 2017; Pfaff et al. 2019; Gupta et al. 2018). A meta-analysis by Samadani and colleagues (2003), for instance, of 13 studies in 381 patients, found a success rate of 96% in brainstem tumor biopsies with only a single case of death. Despite converging evidence for the safety, feasibility, and importance of tumor biopsy in advancing DIPG research, performing these procedures has still been a major clinical bottleneck, limiting the depth and breadth of the DIPG literature and demonstrating the extent to which bureaucratic, ethical, and legal battles are waged in even the most pressing areas of neuroscientific inquiry.
Regardless of the staunch ethical and bureaucratic opposition to advancements in DIPG research, an array of promising therapeutic strategies has been emerging in recent years as the underpinning mechanistic and microenvironmental drivers of DIPG growth have been elucidated (Ballester et al. 2013; Larson et al. 2019; Nagaraja et al. 2017; Sun et al. 2019; Sturm et al. 2012; Tate et al. 2015). Following the landmark findings that epigenetic histone mutations exist in most DIPG tumor cells, and that such H3K27M mutations promote demethylation at particular loci implicated in the oncogenic gene activation of gliomas, one area of focus leverages epigenetic modifying therapies like histone deacetylase and demethylase inhibitors, such as panobinostat, to recover normal trimethylation patterns in DIPG cells (Bender et al. 2013; Lewis et al. 2013). Combination therapies with panobinostat are promising and have been shown to provide better outcomes when paired with reirradiation techniques widely in use already (Wang et al. 2017).
A second area of interest in treating DIPG leverages tumor-specific immunotherapy with developments in peptide vaccines, adoptive T-cells, checkpoint inhibitors, and immunomodulatory antibodies all showing encouraging therapeutic utility (Benitez-Ribas et al. 2018; Brown et al. 2016; Davila et al. 2014; Fried et al. 2018; Kline et al. 2018; Ochs et al. 2017). One such immune modulating antibody, pidilizumab, has had substantial clinical benefit in multiple pediatric cancers and, in a small (n=9) clinical trial for DIPG, increased median overall survival from 9-11 months to an unprecedented 15.6 months (Fried et al. 2018). A third exciting development is the use of Focused Ultrasound (FUS) technology in combination with chemo-, immuno-, and radiotherapies to allow drugs to circumvent the blood brain barrier for direct delivery to areas of malignancy (Englander et al. 2020; Wang et al. 2020). Such studies have shown the safety and feasibility of FUS in creating micro-bubble blood brain barrier openings in animal models, and the first human clinical trials for DIPG are soon to follow. Ultimately, while these studies indicate reassuring advancements in DIPG treatment, they are merely in their infancy, use non-human models, face extreme bureaucratic and financial constraints, and will require immense methodological refinement for further conceptual validation.
Cognitive and Family Burdens
It cannot be understated that the initial diagnosis and hospitalization for pediatric tumors of the central nervous system brings inescapable pain, uncertainty, and distress to both patient and family. Not only can certain tumors be, by virtue of their location or molecular profile, terminal in nature (i.e. DIPG), but even in rare cases in which therapeutic interventions may have clinical efficacy, the risk of long-term cognitive and quality-of-life deficits is severe.
A recent, one-of-a-kind study on 191 DIPG patients, of which only five survived long enough for neurocognitive evaluation, found using various diagnostic measures (of IQ, working memory, and overall academic performance) that almost all had severe deficits placing them in the range of mental retardation (Jackson et al. 2014). In fact, only one patient, significantly older than the others and yet more progressed in tumor infiltration, surprisingly displayed normal cognitive functioning relative to nonclinical, age-based expectations. This finding suggests that neurocognitive deficits attributed to DIPG may not solely depend on the location and extent of the tumor’s spatial infiltration but may also hinge on when the tumor occurs in the patient’s developmental timeline, paired with how disrupting it is to relevant critical periods. While this paper converges with other research noting the role of brain tumors in neurocognitive decline, the evidence for DIPG in this paper is only preliminary. Undoubtedly, its conclusions must be weighed against the study’s limited sample size (n=5) and lack of neurocognitive analysis prior to administration of ionizing radiation, whose risk-factors include well-documented, potentially confounding neurological deficits (Cramer et al. 2019). Furthermore, this study’s cognitive assessments may depend on too narrow and shallow a range of measures, and may need, in order to avoid over- or under-estimation of impairment, to examine patient performance across a more multi-faceted neuropsychological test battery.
A related issue is the authors’ sole use of structural neuroimaging techniques to assess altered neurocognitive performance in DIPG. While the use of T1 and T2 MRI scans confer greater convenience due to their wide clinical use in the diagnosis and treatment of DIPG, the potent plasticity of the pediatric brain during development makes large-scale compensatory network alterations, including those to nearby cortico-striatal and cortico-cerebellar loops, particularly likely as the tumor progresses into thalamic and cerebellar areas. As such, a greater functional or hemodynamic understanding of the brain (via fMRI or PET-based behavioral paradigms) may be central to the vitality of future work in DIPG research. Indeed, limited headway has been made by Hart and colleagues (2019), using resting-state functional magnetic resonance imaging with fractal and connectomics analysis, in understanding network-level alterations in cortical glioma patients. Specifically, they found that brain tumors in multiple spatial locations are associated with peritumoral neural deficits that, as distance from the cancer site increases, are balanced by compensatory overactivation in other regions (i.e. long-range gradients of brain function). While this work was intended to explore the implications of supramarginal surgical resection in cortical brain tumor cases, this study’s analysis of global neural alterations in glioma patients may have important implications for DIPG-related neuroplasticity during childhood development – especially as emerging treatments begin to improve survival rates.
Despite the field’s serious methodological shortcomings in the context of neurocognition, though, we must exercise a certain frankness and charitability towards the reality that DIPG’s near universal lethality makes even the most rudimentary analyses extremely difficult to perform – or of trivial benefit to the quality of life of children with terminal diseases. Such flawed scientific inquiries, then, are not valuable because of the refinement of their design, the robustness of their data, or the adequacy of their statistical power; instead, they are so because they shift the focus of DIPG research beyond its current obsession with pharmacological therapeutics, and increasingly towards recognizing that an infinitely complex web of cognitive, familial, and sociodemographic interconnections may be altered by a pediatric brain tumor.
One element often overlooked by the DIPG literature is the extent to which its dismal prognosis and heart wrenching progression wreak havoc on a child’s parental support system. The unavoidable intellectual declines explored in the preceding paragraph, amongst similar functional impairments with social, cultural, and economic consequence, make it especially anxiety-inducing for parents to grapple with the chronic nature of their child’s ailment. Indeed, emerging literature suggests that parents of children with brain tumors suffer such a loss of confidence, and are so functionally impaired, that they cannot adequately internalize facts, much less make the difficult choices best for their child’s ultimate wellbeing (Barranza et al. 2014; Palmer et al. 2011). While these responses are expected, given the ways in which such moments may fundamentally upend the sense of stability and safety essential to one’s personal life, studies also illustrate that 51% of parents become clinically distressed, perceive reduced quality-of-life during their child’s treatment, and appear at greater risk for developing marital conflicts and post-traumatic stress disorders (Barranza et al. 2014; Fuemmeler et al. 2001; Goebel et al. 2011; Manne et al. 1995). Moreover, parental stress over a child’s brain tumor has been associated with long-lasting psychosocial impacts on the family unit as a whole, evolving family relationships over time, and leading to maladaptive coping strategies, like emotional neglect and self-blame, with sweeping externalities (Cutillo et al. 2018; Shortman et al. 2013). Importantly, the psychological symptoms that often develop in such pressing circumstances can be greater intensified by workplace difficulties, financial adversities, and inadequate systems of social support (Allen et al. 1997; Hoekstra‐Weebers et al. 1998) – suggesting that socioeconomic disparities may underlie an important dimension of this discussion as well.
It is important to note, however, that no study presently explores the intersection between DIPG and biopsychosocial changes to those in closest proximity, loved ones that must often cope with the burdens of this disease for the rest of their lifetimes. Nonetheless, it is not unreasonable to speculate, on the basis of the presented evidence, that such people may be at elevated risk for developing psychiatric disorders and maladaptive coping mechanisms. Still, a series of cross-sectional and longitudinal studies specific to DIPG will be necessary to support these speculations, identify further at-risk populations, and develop effective interventions.
Clinical Trials & Healthcare Equity
Of paramount importance is the stark reality that even the most cutting-edge interventions for DIPG are highly experimental, un-replicated, and still miles away from general practice. For this reason, it is essential to increase funding for both current and novel clinical trials, as only a handful across the country exist today. Nonetheless, the growing reliance of DIPG advancements on evidence from clinical trials (and the same can be said for both cancer and translational neuroscience research more broadly), raises big questions about healthcare equity – particularly when the stakes are so high, the patients are so otherwise helpless, and the trials themselves have been criticized repeatedly for historically low racial and socioeconomic diversity. When resources are so limited and the cost of cancer therapies are continually rising, who should receive potentially life-saving treatment and who should be excluded and left to die? On what foundations are such choices ultimately made and how prone are they to perturbation from practically unalterable characteristics like gender, race, and socioeconomic status? In a world of tremendous population heterogeneity, what can we say about the generalizability and external validity of clinical trials unreflective of this reality? Even further, what steps can we take to leverage current legal precedents, and an increasing sociopolitical consciousness, to end discriminatory clinical trial enrollment in the United States?
So pressing were these questions to the integrity and validity of clinical trials in the United States, that in 1993, the U.S. House of Representatives passed the National Institutes of Health (NIH) Revitalization Act in order to promote the inclusion of women in clinical trials. This added further stipulations to previous government interventions like the Belmont Report and the National Research Act of 1974, that established, among highly important ethics and safety standards, more guidelines for equitable selection of participants in human subjects’ research. While such policy initiatives represented growing social, economic, and gender consciousness within the scientific method, they nevertheless failed in curtailing the effectually discriminatory practices surrounding clinical trial enrollment in the United States. Even today, trials across the country are biased in their choice of participant recruitment across multiple sociodemographic dimensions, and these race-, age-, and gender-based disparities persist in even the most urbanized, multi-cultural areas (Curry & Barker 2007; Murphy et al. 2004; Ramasabbu et al. 2001; Stewart et al. 2007; Taha et al. 2020). This is especially problematic when taken together with considerable evidence suggesting that, for patients with rare malignancies like DIPG, trial enrollment and adjuvant therapy are linked to significantly better patient outcomes (Curran et al. 1993; Davis et al. 1985). Similar disparities are also noted by Curry & Barker (2007), whose chart review of 13,000 brain tumor clinical trial participants in the Cancer Therapy Evaluation Program (CTEP) database, showed a combined Black and Hispanic enrollment in glioma trials of only 4.1%. Indeed, another meta-analysis of 1322 studies in The New England Journal of Medicine found that, on average, clinical trials had a dismal 24.6% rate of female enrollment, and only 14% of them implemented any gender-based analysis whatsoever (Ramasabbu et al. 2001). All together, these studies signify that disparities in clinical trials exist within multiple fields and have not been eliminated by U.S. policy alone. More profoundly, they show that current bureaucratic interventions may solely treat symptoms downstream of the real illness at hand: the patient-doctor relationship.
Key insight from HIV research reveals that significant barriers to clinical trial enrollment exist at numerous, hierarchical levels of organization, from the patient and the physician, to the institution and overall community (King, 2002).Despite well-intentioned efforts at keeping patient care wholly centered on the scientific literature, clinical practice innately harbors a substantial degree of subjectivity. This is because healthcare workers are not only prone to the same prejudices that plague society at large, but their attitudes also underpin important treatment decisions and evoke irreparable feelings of mistrust in disadvantaged populations (King, 2002). Of surprising note is the potency of this dynamic in the informed-consent process of clinical trials, during which mistrusting patients often decline enrollment altogether on the grounds that doing so would curtail their autonomy and limit their legal possibilities in cases of egregious malpractice (King, 2002).Reestablishing trust, then, is central to any discussion addressing healthcare disparities in a body of DIPG research wholly dependent on clinical trial enrollment; doing so not only gives disadvantaged minorities access to potentially life-altering care, but also allows scientists to better understand the disease’s nature across a more diversified population.
Establishing minority trust in healthcare requires an unswerving proactivity and attention to detail. First, professional schools in the health/neurosciences must integrate, as seamless components of their curriculum, fully dedicated courses championing cultural sensitivity, trust building, and bias elimination. Required public service hours, cumulative term projects analyzing disease burdens in local underserved communities, or study abroad programs aimed at exposing students to cultures distinct from their very own, are some amongst an endless body of proposals to consider in the education of emerging providers. Secondly, federal resources must be appropriated towards an independent agency of healthcare contractors with the following duties: review all active clinical trials in conjunction with institutional review boards to identify disparities, observe patient interactions and document areas of improvement, and work in conjunction with the healthcare team to build better habits of intercultural sensitivity. While we must be careful to avoid the chilling effects that arise when external entities “enforce” or issue “severe consequences” in cases of misconduct, we must also accept that increased accountability lies at the heart of rebuilding trust and effectively serving patients. Lastly, hospitals must be incentivized to hire a diversified healthcare team better reflective of the American populace, creating a system in which patients are treated by their very own, people who understand not only their physiology, but also the impossible complexities of their lives that drive their actions.
Indeed, it is only by reexamining the moral and ethical imperatives underpinning why we conduct translational neuroscience in the first place that we can act with integrity and justice, better meet the needs of society, and reform the outdated conventions surrounding clinical trial enrollment in this country. The changes outlined above are by no means a definitive cure to healthcare disparities, as sociocultural transformations of this kind are never achieved unilaterally; rather, these proposals serve as a powerful first step in establishing renewed faith in the patient-physician relationship. It is only by restoring the public’s faith in the moral purity and impartiality of clinical trials that research on DIPG, fundamentally dependent on them, can begin to prosper.
Concluding Remarks
At a time when perpetual therapeutic advancements in neurosurgery and neuro-oncology are the norm, my sincere hope in exploring these topics has been tripartite: to raise awareness about a highly unacceptable deficit in cancer treatment today, to encourage further research and funding for a new generation of budding physician-scientists, and to expose current inequities in translational neuroscience in order to eliminate them moving forward. This is because the goals of current and future neuroscientists are inexorably linked to the fate of real human beings, and their success and failures. As such, our clinical and scientific preoccupations, in order to provide true value to the lives of those whose minds we hope to better understand, must align itself with fundamentally human questions. What steps must be taken in the coming years to eliminate the ever-present threat of DIPG for good? With the cost of cancer therapies continually rising, how can we minimize the extent to which external socioeconomic influences wreak havoc on families at the front lines of battle? Additionally, what steps can we take to leverage current legal precedents, and an increasing sociopolitical consciousness, to end discriminatory clinical trial enrollment in the United States? As we take “one small step for man, one giant leap for mankind” in the treatment of DIPG, these are the types of questions we must perpetually ask. For now, we must assemble a global coalition of clinician-scientists, federal agencies, social workers, and professional schools to lead us into a new golden age of neuroscientific exploration, where patient trust is paramount, and where DIPG is nothing more than a disease of the past.
Deep Thought 