the Challenge
Bart Lutters and Marike L. D. Broekman
Introduction
In 1886, the renowned English neurosurgeon Sir Victor Horsley (1857–1916) first used direct electrical stimulation to identify the primary motor cortex of a patient suffering from Jacksonian epilepsy [1]. The patient was awake while Horsley per- formed a craniotomy and subsequently applied faradic current to his brain. Following the initial report, awake craniotomies—combined with direct cortical stimulation—
were soon adopted for the surgical management of glioma patients. Today, the pro- cedure is regarded an effective method to identify indispensable brain regions, thereby minimizing the occurrence of postoperative functional deficits.
As evidence-based physicians, we owe to our current and future patients the continuous engagement in efforts to improve and evaluate the therapies we subject them to. The evaluation of awake craniotomies, however, confronts us with various scientific and ethical challenges. For one, the use of powerful research designs, such as the randomized controlled trial, may not be suitable due to a perceived lack of equipoise, lack of structured outcome collection, and small study populations.
Ethical concerns regarding the informed consent process, therapeutic misconcep- tion, and patient vulnerability further complicate awake craniotomy research.
In 2007, the Institute of Medicine introduced the learning health system (LHS), a system in which “knowledge generation is so embedded into the practice of medi- cine that it is the natural product of the healthcare delivery process and leads to the continuous improvement of care” [2]. Key components of the LHS include the search for alternatives to large randomized controlled trials, implementation of sys- tem databases, and fostering understanding of evidence-based medicine [2]. Here, we aim to identify the scientific and ethical challenges associated with awake crani- otomy research in glioma patients and to propose the LHS and its associated ethics framework as a potential way to overcome some of these challenges.
Perceived Lack of Clinical Equipoise
The awake craniotomy procedure is commonly regarded as an effective method to minimize postoperative deficits and has, therefore, been widely adopted by the neu- rosurgical community. Despite its general acceptance, RCTs comparing the awake procedure to resection under general anesthesia have not been conducted. In con- trast to the introduction of new pharmaceuticals, surgical innovation and research often take place outside controlled study conditions [3]; surgical techniques are commonly introduced with little or no ethical oversight, and if the opportunity for timely evaluation is not seized, the procedure may be adopted by the medical com- munity without proper evidence [4]. This is also the case for awake craniotomies;
since there is no genuine disagreement about the superiority awake craniotomies for the resection of gliomas within or nearby indispensable brain regions, most neuro- surgeons feel that it would be unethical to expose patients to the procedure under general anesthesia instead [5–7]. Due to this perceived lack of clinical equipoise, large RCTs are not feasible, stressing the need for suitable alternatives.
The LHS has proposed several alternatives to the randomized controlled study design, including the cluster randomized trial (CRT) [2]. CRTs do not require ran- domization at patient level but allow participating institutions to perform their pre- ferred standard of care. For instance, an institute which would favor glioma resection under general anesthesia would be compared to an institute preferring the awake pro- cedure. This study design has several limitations, as the absence of randomization reduces the internal validity of the study. That being said, it seems preferable to sup- plement evidence from RCTs with high-quality nonrandomized studies, rather than solely relying on clinical opinion whenever randomized trials are not feasible [2].
Lack of Structured Data Collection and Sharing
Even though the awake craniotomy procedure—combined with direct cortical and subcortical stimulation—is widely regarded as the preferred treatment for gliomas within or nearby eloquent brain regions, technical details of the procedure vary
significantly among institutions. Whereas some institutions reserve the procedure for tumors in proximity to essential brain regions (e.g., motor cortex, somatosen- sory cortex, language regions), others rely on awake craniotomies for most glioma resections, independent of tumor location [5]. Moreover, the extent of brain expo- sure, the use of intraoperative tasks, and the application of direct electrical stimula- tion vary among institutions and among surgeons from the same institution. These practice variations could—when properly registered and shared—be harnessed for the evaluation of the awake craniotomy procedure.
The LHS supports the implementation of large system databases and universal electronic health records, thereby providing a platform for continuous learning based on clinical decision-making. For resective glioma surgery, this would include the systematic registration of patient baseline information, tumor location, extent and type (awake versus general anesthesia) of craniotomy performed, direct stimu- lation protocol (including positive and negative stimulation sides), and treatment outcome in terms of postoperative functional impairment and tumor survival.
Adequate registration and sharing of this data would potentially allow for the gen- eration of evidence by means of observational treatment comparisons (OTC), in which outcomes from patients can be compared across institutions.
Informed Consent
Adequate informed consent for participation in any research activity should ideally consist of three components: (1) the surgeon must disclose evidence-based informa- tion regarding the risks and benefits associated with the procedure and reasonable alternatives, (2) the candidate subject should be capable of weighing the risks and benefits associated with the procedure, and (3) the candidate subject should volun- tarily consent to the procedure, that is, the decision to participate should reflect his or her own opinion [8]. The informed consent process for awake craniotomy research is particularly challenging and hindered in various ways.
First, as no RCTs have been conducted on awake craniotomies, it is challenging for the neurosurgeon to disclose accurate information regarding the risks and ben- efits associated with the procedure. Disclosure becomes even more difficult when the surgeon wishes to investigate a modification to the existing awake craniotomy procedure, as the results of the modification cannot possibly be predicted. In such case, the neurosurgeon should always provide the information regarding his or her limited experience with the procedure. In addition, personal interests (e.g., career opportunity, financial gain, social status) may cause some involved in the evaluation of awake craniotomies to overstate the benefits and downplay the risks associated with the research activity.
The remaining two elements of informed consent—decisional capacity and vol- untariness—give rise to additional ethical challenges, as glioma patients nominated for surgery represent a particularly vulnerable patient group. Indeed, it is conceiv- able that recently diagnosed glioma patients may not be in “the right psychological state of mind” to adequately weigh the risks and benefits associated with a certain
research activity. The neurological nature of the disease and its therapy may further interfere with the patient’s decisional capacity. Lastly, with regard to voluntariness, it has been shown that glioma patients often base their consent to a research activity on trust in their physician or on the idea that dissent would harm their doctor-patient relationship, rather than on the information disclosed by the neurosurgeon [8].
The LHS may help to overcome at least some of these challenges by “improving public understanding of the nature of evidence-based medicine […] and the impor- tance of supporting progress toward medical care that reflects the best evidence”
[2]. “Patients participating in clinical research often misconceive a research activity to be a form of clinical care tailored to their individual medical needs.” For instance, glioma patients may expect to receive certain benefits from participating in a cluster randomized trial or an observational treatment comparison, whereas, in reality, only future patients are likely to benefit [9]. Increased awareness of the nature of evidence- based medicine could potentially lessen this “therapeutic misconception”
and smoothen the informed consent process, as informed patients would be able to take a general stance toward participating in research activities before the circum- stances arise. In addition, the LHS encourages healthcare workers to similarly adopt an open attitude toward evidence generation and self-reflection, thereby potentially diminishing the influence of the personal interests on the informed consent procedure.
Discussion
Since the Belmont Reports of the 1970s, the field of bioethics has traditionally drawn a strict boundary between clinical research and care, the first being primarily concerned with the development of generalizable knowledge and the latter to ben- efit the individual patient [10]. Clearly, various scientific and ethical challenges are encountered in evaluating the awake craniotomy procedure in glioma patients,
“stressing the need to rethink the way in which neurosurgical research and care is currently organized.” We believe the LHS may provide a way to address the above- mentioned challenges while realizing that too much focus on learning activities may expose patients to disproportionate risks, abuse, and unjust distribution of burdens [11]. Consequently, Faden et al. have recently proposed an ethics framework to help ensure that research activities within a LHS are conducted in an ethically acceptable fashion [11].
The ethics framework by Faden and coworkers significantly departs from tradi- tional bioethics in two ways: (1) the framework places a moral emphasis on learning and (2) sets a moral obligation to address unjust distribution of burdens within the healthcare system [11]. The moral obligation to learning includes both patients and healthcare professionals and holds that everyone involved in healthcare—both on the receiving and the providing end—had the moral responsibility to contribute to learning activities in order to enhance clinical practice “or the value, quality, or efficiency of the systems, institutions, and modalities through which health care services are provided” to the benefit of future patients [11]. This approach may
somewhat temper traditional guidelines of ethical oversight and consent, thereby stimulating continuous learning activities to take place through the implementation of large system databases and data sharing.
The moral obligation to address unequal burdens within the healthcare system holds that healthcare workers and institutions have the responsibility to prevent that
“the risks and burdens associated with a learning activity fall disproportionally on patients that are already disadvantaged” [11]. The widespread implementation of large system databases and universal electronic healthcare records carries with it the potential risk of taking unfair advantage of patients who are already particularly vulnerable to the undue influence of others. As mentioned earlier, glioma patients nominated for brain surgery represent a particularly vulnerable patient group, due to the severity and the disabling nature of their disease [12]. The obligation to address unjust inequalities will help to ensure that the burdens and benefits of continuous research activities will be equally distributed among patients and institutions “rather than placing the burden primarily on most desperate and refractory individuals” or on the less prosperous institutions.
Conclusion
Evaluating the awake craniotomy procedure in glioma patients confronts us with various scientific and ethical challenges. Here, we aimed to identify these chal- lenges—namely, (1) a perceived lack of clinical equipoise, (2) a lack of structured data collection and sharing, and (3) an ineffective informed consent process—and to propose the concept of a learning health system as a potential solution. Firstly, the use of alternatives to large randomized studies—such as cluster randomized trials and observational treatment comparisons—proposed by the LHS may enhance awake craniotomy procedure research by filling in the gaps of evidence when RCTs are infeasible. The implementation of system databases and universal electric health records may further stimulate learning activities. Moreover, we believe that foster- ing an improved public and professional understanding of the nature of evidence- based medicine would smoothen the informed consent process and lessen the
“therapeutic misconception.” Finally, we believe that the ethics framework pro- posed by Faden and coworkers will minimize the risks associated with the blurring of the traditional boundaries between research and care while warranting the “do no harm” principle.
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