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. 2025 Aug 16;13(1):3–13. doi: 10.1093/nop/npaf085

Ethical considerations in randomization for neurosurgical oncology trials: A scoping review

Nathan A Shlobin 1,#,✉, Mira C Hasner 2,3,#,✉, Philipp Karschnia 4,5, Georg Widhalm 6, George E D Petrescu 7,8, Philippe Schucht 9, Thiebaud Picart 10,11, Marian C Neidert 12, Jens Gempt 13, Rachel Grossman 14, Asgeir S Jakola 15, Michael D Jenkinson 16, Roland Goldbrunner 17, Michael Weller 18, Johnny Duerinck 19, Marike L D Broekman 20,21,22
PMCID: PMC12965654  PMID: 41798128

Abstract

Background

Increased interest in randomized controlled trials (RCTs) in neurosurgical oncology represents a significant advancement in the promotion of rigorous interventions in the field. However, the concept of randomization in neurosurgical oncology contains numerous ethical considerations. In this scoping review, we characterize the landscape of ethical challenges in randomization for neurosurgical oncology trials, highlight gaps in the literature, and delineate best practices for approaching randomization in these trials with a focus on the role of alternative study designs.

Methods

A scoping review was conducted using the PubMed, Embase, and Scopus databases. Titles and abstracts were screened for relevance. Studies meeting prespecified inclusion criteria underwent full-text review. Relevant data were extracted.

Results

Of 546 resultant articles, 20 were included. Seven (35%) studies focused on limitations of RCTs, 6 (30%) on utility of randomization, 4 (20%) on alternative designs, and 3 (15%) on informed consent. Randomization involves intrinsic ethical challenges in addition to practical challenges specific to neurosurgical oncology, including unrepresentative study populations, uncertainty regarding equipoise, and the inability to attain informed consent. Alternative study designs include preliminary prospective cohort studies with specific properties, on/off studies, seamless phase II/III trials, window-of-opportunity trials, and adaptive randomization models.

Conclusions

Randomization in neurosurgical oncology RCTs is ethically challenging. RCTs are most useful when they significantly enhance the quality of evidence and have the potential to be practice-changing. When RCTs are the preferred study design, proper design and implementation may mitigate ethical challenges. In some cases, alternative study designs may advance research while safeguarding ethical priorities.

Keywords: brain tumor, medical ethics, neurosurgery, neuro-oncology, randomization

Key Points.

  • Randomization in surgical RCTs in neuro-oncology presents significant ethical challenges.

  • Population-specific adaptation of trial designs can ensure randomized trials and meet the requirements of ethically sound research.

  • Alternative trial designs may better balance ethical imperatives with feasibility in some cases.

Several considerations limit the conduct of randomized controlled trials (RCTs) in neurosurgical oncology. A primary obstacle is the lack of collective clinical equipoise, as uncertainty about the most effective treatment is not clearly established.1 The procedural variability of surgery complicates randomization and leads to the perception that surgical innovation is unsuitable for RCTs. Complexity and relative rarity of disease further impede comparing outcomes and lead to low randomization rates, underutilization of controls, and overestimation of effect sizes.2

Standardization of surgical procedures is further complicated by variations in surgical techniques, resources, learning curves,3,4 anesthesia techniques, and in pre- and postoperative care. The decision to perform surgery depends on the condition being treated, patient characteristics, and the surgeons’ experience and skill. Importantly, surgical innovation differs from traditional medical research as it is intimately embedded in clinical practice.1 Neurosurgical developments historically evolved through incremental adjustments rather than formal trials, limiting regulatory oversight to navigate conflicts of interest.5 Neurosurgical oncology patients are particularly vulnerable, due to their often-poor prognosis despite receiving the best available care. Randomization of treatment is often complicated by strong patient preference for experimental treatment and the inherent difficulty of blinding surgical interventions.

Despite these hurdles, the interest in conducting trials for neurosurgical oncology is increasing, marking a significant advancement in the systematic evaluation of neurosurgical interventions in neuro-oncology.6–17 No study has summarized the ethical challenges of randomization in neurosurgical oncology trials. Distinguishing whether ethical challenges for a given study objective stem from external factors, such as patient population characteristics, or are intrinsic to randomization itself (equipoise, informed consent, and trial design) helps to determine when alternative study designs may be more appropriate. This scoping review characterizes the landscape of these challenges, highlights gaps in the literature, and delineates best practices for mitigating challenges to facilitate a path forward for the conduct of trials in neurosurgical oncology.

Materials and Methods

A scoping review was the chosen method for this study given the abstract nature of the topic, heterogeneity of the literature, and presence of gaps in the literature. This approach involves the same rigorous database search and screening process as a systematic review, but is more appropriate for comprehensive reviews of broader topics.18

The review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews to investigate the ethics of randomization in neurosurgical oncology trials.19 PubMed MEDLINE (National Library of Medicine), Embase (Elsevier), and Scopus (Elsevier) were searched on September 11, 2024. Search terms were designed using the Population, Concept, and Context (PCC) framework, and are displayed in Table 1.

Table 1.

Search Terms

Database Search terms
PubMed (“brain neoplasms”[MeSH] OR “brain neoplasm*”[tiab] OR “intracranial neoplasm*”[tiab] OR “brain tumor*”[tiab] OR “intracranial tumor*”[tiab] OR “neuro-oncolog*”[tiab] OR “glioma*”[tiab] OR “glioblastoma*”[tiab] OR “astrocytoma*”[tiab] OR “ependymoma*”[tiab] OR “medulloblastoma*”[tiab] OR “oligodendroglioma*”[tiab] OR “acoustic neuroma*”[tiab] OR “acoustic schwannoma*”[tiab] OR “vestibular neuroma*”[tiab] OR “vestibular schwannoma*”[tiab] OR “craniopharyngioma*”[tiab] OR “pineocytoma*” OR “pineoblastoma*”[tiab] OR “pituitary adenoma*”[tiab] OR “atypical teratoid rhabdoid tumor*”[tiab] OR “meningioma*”[tiab] OR “brain metastas*”[tiab])
AND
(“neurosurgery”[Mesh] OR “neurosurgical procedures”[MeSH] OR “neurosurg*”[tiab] OR “neurological surg*”[tiab] OR “surg*”[tiab] OR “resect*”[tiab] OR “biops*”[tiab] OR “craniotom*”[tiab])
AND
(“Randomized Controlled Trial”[Publication Type] OR “random allocation”[MeSH] OR “Clinical Trials as Topic”[MeSH] OR “Clinical Trial Protocols as Topic”[MeSH] OR “randomized controlled trial*”[tiab] OR “randomized clinical trial*”[tiab] OR “random allocat*”[tiab] OR “randomly allocat*”[tiab] OR “randomiz*”[tiab] OR “randomis*”[tiab] OR “study design”[tiab] OR “trial design”[tiab])
AND
(“bioethics”[MeSH] OR “ethics, medical”[MeSH] OR “informed consent”[MeSH] OR “therapeutic equipoise”[MeSH] OR “medical futility”[MeSH] OR “resource allocation”[MeSH]
OR “ethic*”[tiab] OR “bioethics*”[tiab] OR “informed consent*”[tiab] OR “consent”[tiab] OR “equipoise*”[tiab] OR “futil*”[tiab] OR “resource allocat*”[tiab] OR “allocate resource*”[tiab] OR “health care ration*”[tiab] OR “cost-effective*”[tiab] OR “cost effective*”[tiab] OR “resource management”[tiab])
Embase (“brain neoplasm*” OR “intracranial neoplasm*” OR “brain tumor*” OR “intracranial tumor*” OR “neuro-oncolog*” OR “glioma*” OR “glioblastoma*” OR “astrocytoma*” OR “ependymoma*” OR “medulloblastoma*” OR “oligodendroglioma*” OR “acoustic neuroma*” OR “acoustic schwannoma*” OR “vestibular neuroma*” OR “vestibular schwannoma*” OR “craniopharyngioma*” OR “pineocytoma*” OR “pineoblastoma*” OR “pituitary adenoma*” OR “atypical teratoid rhabdoid tumor*” OR “meningioma*” OR “brain metastas*”):ti,ab,kw
AND
(“neurosurg*” OR “neurological surg*” OR “surg*” OR “resect*” OR “biops*” OR “craniotom*”):ti,ab,kw
AND
(“randomized controlled trial*” OR “randomized clinical trial*” OR “random allocat*” OR “randomly allocat*” OR “randomiz*” OR “randomis*” OR “study design” OR “trial design”):ti,ab,kw
AND
(“ethic*” OR “bioethics*” OR “informed consent*” OR “consent” OR “equipoise*” OR “futil*” OR “resource allocat*” OR “allocate resource*” OR “health care ration*” OR “cost-effective*” OR “cost effective*” OR “resource management”):ti,ab,kw
Scopus TITLE-ABS-KEY(
(“brain neoplasm*” OR “intracranial neoplasm*” OR “brain tumor*” OR “intracranial tumor*” OR “neuro-oncolog*” OR “glioma*” OR “glioblastoma*” OR “astrocytoma*” OR “ependymoma*” OR “medulloblastoma*” OR “oligodendroglioma*” OR “acoustic neuroma*” OR “acoustic schwannoma*” OR “vestibular neuroma*” OR “vestibular schwannoma*” OR “craniopharyngioma*” OR “pineocytoma*” OR “pineoblastoma*” OR “pituitary adenoma*” OR “atypical teratoid rhabdoid tumor*” OR “meningioma*” OR “brain metastas*”)
AND
(“neurosurg*” OR “neurological surg*” OR “surg*” OR “resect*” OR “biops*” OR “craniotom*”)
AND
(“randomized controlled trial*” OR “randomized clinical trial*” OR “random allocat*” OR “randomly allocat*” OR “randomiz*” OR “randomis*” OR “
study design”
OR “
trial design”
)
AND
(“ethic*” OR “bioethics*” OR “informed consent*” OR “consent” OR “equipoise*” OR “futil*” OR “resource allocat*” OR “allocate resource*” OR “health care ration*” OR “cost-effective*” OR “cost effective*” OR “resource management”))
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Duplicates were removed, and remaining articles were screened by title and abstract for relevance, followed by full text review based on prespecified eligibility criteria. Inclusion criteria were articles written in English, published in journals, discussing ethical considerations in randomized neurosurgical oncology trials or in surgical trials that could be applicable to neurosurgical oncology. Articles discussing challenges in RCTs or alternative trial designs that were applicable to neurosurgical oncology or guidelines/reviews from collaborations such as the IDEAL collaboration were also included. Exclusion criteria were abstracts, book chapters, nonsurgical interventions, no focus on neuro-oncology, and study designs other than clinical trials. During both stages of screening, articles were screened by 2 independent reviewers, and all conflicts were resolved via discussion.

Data, including bibliographic data, population, intervention, and ethical considerations, were extracted. Data were grouped thematically for analysis.

Results

Of 546 resultant articles, 20 were included (Figure 1).20–39 No assessments of methodological quality and risk of bias were performed, as is standard for scoping reviews.18 All included studies are shown in Table 2. A total of 11 studies (55%) were reviews, 5 (25%) editorials, 2 (10%) surveys, and 1 (5%) each survey and randomized study. Eleven studies (55%) discussed topics related to neurosurgery, and 6 (30%) focused specifically on neuro-oncology. Seven (35%) studies focused on limitations of RCTs, 6 (30%) on utility of randomization, 4 (20%) on alternative designs, and 3 (15%) on informed consent.

Figure 1.

Figure 1.

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PRISMA-SR flowchart. This flowchart outlines the search and selection process for this scoping review.

Table 2.

Included articles

Manuscript Article type Category Disciplinary focus Key arguments
Bernstein, 2005 (20) Editorial Informed consent Surgical Fully informed consent is rarely met because disclosure, capacity, and voluntariness are rarely completely respected
Cote et al., 2016 (21) Editorial Informed consent Neurosurgery Unproven innovative treatments may pose risk of harm, but patients may feel compelled to try them
Gupta et al., 2017 (22) Review Alternative designs Neuro-oncology “On/off” studies, seamless phase II/III studies, and Bayesian adaptive randomization models may mitigate ethical challenges of randomization
Hachem and Bernstein, 2020 (23) Editorial Trial design Neurosurgery RCTs may exclude certain populations like geriatric patients
Kiehna et al., 2010 (24) Review Utility Neurosurgery RCTs may stifle innovation
Lilford et al., 1995 (25) Review Trial design No specific focus Individual equipose1 is different from collective clinical equipoise2
Mansouri et al., 2020 (26) Survey Trial design Neurosurgery 69.2% of respondents indicated collective clinical equipoise2 does not exist for a surgical RCT in diffuse low grade gliomas
Mansouri et al., 2016 (27) Review Utility Neurosurgery Neurosurgical RCTs are low quality
Mitchell et al., 2005 (28) Review Utility Neurosurgery Ethical considerations may restrict the ability of RCTs to be performed
Muskens et al., 2017 (29) Systematic review Alternative designs Neurosurgery RCT may not be the preferred study design and is not feasible for some neurosurgical interventions; Case-matching studies, controlled interrupted time series designs, and modified RCTs are alternatives
Paez et al., 2022 (30) Review Alternative designs No specific focus RCT is feasible in certain circumstances, but IDEAL 2b studies should be used where it is not
Patel et al., 2021 (31) Review Trial design Neurosurgery Only 51% of respondents were willing to include an example patient in an RCT comparing repeat surgery with nonsurgical options
Raman et al., 2020 (32) Randomized study Utility Neuro-oncology Randomization may not illustrate any survival difference for patients with brain metastases due to limited prognosis of target population and effectiveness of salvage treatments
Sherratt et al., 2020 (33) Survey Trial design Neuro-oncology Difficult to convey equipoise or to present risks/benefits without sounding biased
Song and Wen, 2023 (34) Review Alternative designs Neuro-oncology Window of opportunity trials, basket and bucket trials, and platform trials using Bayesian adaptive reasoning may be useful
Takroni et al., 2022 (35) Review Trial design Neurosurgery The distinction between collective clinical and individual equipoise is important
Thavarajasingam et al., 2023 (36) Review Utility Neuro-oncology Randomization may increase the validity of findings
Tewarie et al., 2020 (37) Editorial Utility Neurosurgery RCTs may reframe the reliance on low-quality guidelines
Vooijs et al., 2023 (38) Editorial Informed consent Neuro-oncology Therapeutic misconception may underlie motivation to participate in an RCT
White et al., 2024 (39) Review Trial design Neurosurgery Collective clinical equipoise2 is the important type of equipoise
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RCT, randomized controlled trial.

1. Individual equipoise reflects the lack of preference or uncertainty about benefits and harms of a treatment by the clinician involved in the research study.

2. Collective clinical equipoise is the collective opinion among clinicians that none of the interventions is superior.

Limitations of RCTs

Seven studies explored the limitations of RCTs. Certain populations, such as geriatric patients, may be systematically excluded from RCTs,23 reducing generalizability and the effectiveness of implementation of RCTs. Exclusion of subgroups is often based on ethical considerations. It would, for example, be unethical to subject an elderly patient to the associated risks of a trial studying supramaximal resection, when it is thought that this patient is unlikely to derive substantial benefit from a more aggressive treatment form. The other studies discussed equipoise and potential conflicts of interest.

Three studies highlighted the distinction between collective clinical equipoise and individual equipoise. Collective clinical equipoise is often described as a collective opinion among clinicians that none of the interventions is superior, while individual equipoise reflects the lack of preference or uncertainty about the benefits and harms of a treatment by the clinician involved in the research study.25,35,39 However, these studies emphasized that collective clinical equipoise is the ethically relevant form of equipoise. Moreover, there are differences about what constitutes collective clinical equipoise. Mansouri et al. highlighted that only 30% of respondents believed equipoise exists for a surgical RCT in diffuse low-grade gliomas,26 while Patel et al. reported that only half of respondents were willing to include an example patient in an RCT comparing repeat surgery with nonsurgical treatments.31

Five studies described the role of potential conflict of interest. Clinicians taking on both the role of primary caregiver and the researcher conducting a trial must remain vigilant of internal conflicts of interest and subtle forms of coercion.20 The integrity of the clinician-patient relationship may be subject to clinician-researchers experiencing conflict between personal and collective equipoise.25 Sherratt et al. noted that presenting risks and benefits or conveying the existence, or lack thereof, of equipoise is challenging without leading potential participants to perceive bias.33 White et al. further emphasize the power dynamics inherent in research partnerships, regarding patient engagement and the relationship between neurosurgeons and the industry. Although neither are problematic by definition, careful assessment is required to mitigate the risk of unintended exploitation and bias.39 Takroni et al. argue that RCTs could use mixed funding models with both support from non-profits and the industry, to reduce the influences of bias and financial conflict of interest introduced by industry funding.35

Informed consent

Three studies discussed informed consent for randomization.20,21,38 Bernstein et al. argued that truly informed consent in clinical trials is essentially impossible.20 He noted 3 elements of informed consent, which may carry overlap with challenges in nonsurgical trials: disclosure, capacity, and voluntariness. Regarding disclosure, investigators could not list every possible risk of an experimental therapy because they cannot foresee certain risks and often overemphasize potential benefits while underemphasizing potential risks. For capacity, patients might not be in a psychological state of mind to understand all the information they receive regarding a trial, and cognitive deficits may further complicate patient understanding. About voluntariness, patients may experience undue influence from others and may unduly influence themselves due to what they perceive others may want. Vooijs et al. highlighted that therapeutic misconception, the decision to enter a study for individual benefit even though individuals may be randomized to a control arm, may render randomization fraught.38 Cote et al. emphasized that even though unproven treatments may pose a risk of harm, individuals with end-stage neuro-oncological disease may feel compelled to try them.21

Utility of randomization

Six studies investigated the utility of randomization, evaluating the application and scientific validity of RCTs.24,27,28,32,36,37 RCTs have the benefit of increasing the validity of findings36 and can reframe the reliance on low-quality guidelines if performed in a high-quality manner.37 However, most RCTs in neurosurgery, including neurosurgical oncology, are of low scientific value because they are underpowered.27 Randomization may also fail to illustrate differences depending on the patient populations chosen or the effectiveness of previous interventions.32 RCTs in the surgical treatment of malignant glioma are scarce due to ethical concerns.28 These concerns include awareness of limitations of RCTs such as generalizability, costs, duration, as well as specific ethical challenges related to neurosurgical oncology, such as perceived lack of equipoise. The rigid structure and duration of RCTs may also stifle innovation if the advancement of neurosurgical oncology treatments is predicated on having an RCT in support of an intervention.24

Alternative trial designs

Four studies delineated alternative designs to RCTs.22,29,30,34 In cases when RCTs are not feasible, for example, IDEAL 2B studies, which are preliminary prospective collaborative cohort studies with certain properties, may be used to investigate treatment effects.30 While IDEAL 2B studies share exploratory objectives with Phase II trials, they are tailored to surgical innovation and may use observational designs, necessitating strict inclusion criteria and standardized prospective follow-up to reduce bias. The Surgical IDEAL Collaboration promotes the structured, ethical evaluation of surgical innovations through a phased framework, ensuring safe and effective implementation. IDEAL 2B studies include assessment of a new technique or technology with incorporation of stakeholder values, determining the appropriateness of progressing to an RCT or pilot study.40 RCTs may be modified to enhance the ethical suitability of randomization.29 “On/off” studies, in which patients are compared to themselves in a control and intervention condition, and case-matching studies, in which individuals undergoing an intervention are compared to individuals not undergoing the intervention who are matched on key characteristics, may allow more individuals to obtain the treatment benefit of an RCT while limiting the number of participants required to demonstrate an effect.22,29 Seamless phase II/III studies, involving comparison of multiple interventions to a control (exploratory stage), followed by comparison of the most effective or safe intervention to a control (confirmatory stage), and shared control arms may also limit the number of participants required.22 Window-of-opportunity trials, which investigate the time period after diagnosis but before intervention, may render randomization appropriate by minimizing time without a potentially effective intervention.34 Adaptive randomization models, such as Bayesian models, attempt to change the probability of allocation to a specific group based on the treatment effect,22,34 allowing minimization of the number of participants required to understand the utility of a treatment.

Discussion

Generalizable, relevant, high-quality data are needed to improve neurosurgical treatment for neuro-oncology patients. This scoping review presents the ethics of randomization in neurosurgical oncology trials and highlights substantial gaps in the literature. While randomization is feasible in some instances and remains the gold standard for proving the effectiveness of an approach, its ethical application in neurosurgical oncology requires careful consideration. As such, RCTs can provide robust evidence for effective surgical approaches when applied appropriately. We propose alternative study designs to meet the requirements of ethically sound research for studies where RCTs are unsuitable.

Ethical challenges in randomization

Distinguishing which ethical issues arise from extrinsic factors and which are inherent to the process of randomization, such as equipoise, informed consent, and trial design, can provide guidance. Concerns regarding equipoise are grounded in the principles of beneficence and non-maleficence.41 Implementation of equipoise is challenged by its dependence on subjective expert opinions, lack of consideration of treatment costs,42 and disagreement regarding what constitutes clinical equipoise.26,31 Rather than unanimous agreement that there is no superior treatment, collective clinical equipoise often underscores variability in clinicians’ views and management. The lack of perceived collective equipoise impedes the conduct of certain RCTs, such as those comparing submaximal resection to biopsy. Generating high-quality evidence, in the traditional sense, may thus be more difficult in neurosurgical oncology than in certain medical disciplines. The principles of equipoise and futility emphasize that while patients in the advanced stage of their disease should have access to innovative surgical treatment via clinical trials,21 experimental treatments should offer a reasonable probability of clinical benefit. Improving our understanding of novel surgical interventions should not precede general considerations about what constitutes good care.

The lack of consensus regarding what constitutes futility in neuro-oncology marks a notable gap in the literature. While tools like the Karnofsky Performance Status43 and multidisciplinary conferences inform clinical decision-making, we need objective and standardized ways to decide, based on surgical neuro-oncological trial results, when a treatment is not providing benefit to patients.44,45 Initiatives such as the response assessment in neuro-oncology group46 have advanced such efforts.

Obtaining informed consent in a neurosurgical oncology cohort is difficult due to the complexity of information that must be conveyed, the uncertainty inherent to neurosurgical outcomes, and cognitive impairment affecting many patients.47 Poor prognosis may increase the vulnerability of patients in advanced stages of disease. For many, enrollment in a clinical trial represents a final hope, heightening the risk of therapeutic misconception and unintentional coercion. Navigating these risks requires careful communication, as the inability to attain true informed consent from patients is a hazard to the principle of autonomy.

Ethical considerations raised in RCTs are closely tied to study objectives and vary with the degree of divergence between trial arms. Trials comparing different surgical modalities, like biopsy versus resection, raise more ethical questions than trials comparing different surgical methods where patients receive the same baseline intervention, such as resection with 5-ALA versus white light or the use of intraoperative MRI (iMRI).7,8,10

A crucial hazard to randomization is the limited generalizability resulting from patient-specific factors affecting treatment response, such as tumor type, location, stage, advancing molecular classification48 and comorbidities. Standardized RCT protocols may fail to address the complexity and personalized aspects of neuro-oncological care.49 To account for potential confounders, specifically for survival endpoints, study populations may become highly specific and generate unrepresentative outcomes. Vulnerable subgroups, such as the elderly23 or patients with prognostic uncertainty, are often excluded, violating the social validity of the study through lack of representation of the clinical neuro-oncological treatment population.50

Harnessing alternative designs

When conducted rigorously, RCTs can fulfill all 7 criteria for ethically sound research, as outlined by Emanuel et al.: (1) social or scientific value, (2) scientific validity, (3) fair subject selection, (4) favorable risk–benefit ratio, (5) independent review, (6) informed consent, and (7) respect for enrolled participants.50 However, given that their utility heavily depends on the objectives, population, and interventions of the study, they may not always be the best design to generate high-quality evidence in neurosurgical oncology. Modifying RCTs or considering alternative trial designs may not only address the ethical challenges of randomization but also improve the quality of trials.

For example, IDEAL 2B studies30 gather observational clinical data through collaborative cohort studies. The FUTURE-GB trial studies intraoperative use of enhanced imaging techniques, using an IDEAL 2B framework during its pilot, followed by a composite endpoint of deterioration-free survival.11 This demonstrates neuro-oncology is well-suited for trials with survival endpoints, given the high mortality rates comparable to neurotrauma, where researchers have achieved high patient enrollment.

Other study designs retain randomization but seek to reduce ethical concerns arising from treatment accessibility, equitable risk-distribution, and exposure to prolonged uncertainty through methods that expand treatment arms, increase efficiency, or incorporate response-adaptive mechanisms, as depicted in Table 3. These include “on/off” and case-matching studies,22,29 seamless phase II/III trials,22 window-of-opportunity trials34 and adaptive randomization models.22,34 The use of external data as controls in shared control arms requires a high degree of coordination across studies, but could provide a solution in the context of rare disease. When carefully matched, external controls may also help to account for patient heterogeneity, particularly when combined with Bayesian methods that allow for individualized inference and subgroup modeling.22,51,52 Cluster randomized trials can be used to ensure that all sites adhere to best practices while addressing significant variations in specific aspects, ensuring other factors remain comparable across clusters. A prospective cohort study comparing iMRI-guided resection and 5-ALA guidance14 generated a large sample size and may be more impactful in shaping clinical practice than an RCT on iMRI with a limited sample size.10

Table 3.

Alternative trial designs

Study design Description Advantages Limitations Example
RCT Randomized assignment of groups to treatment arms Reduce bias by minimizing differences between groups Ethical concerns in vulnerable populations; infeasible when equipoise is lacking Stummer et al.(7); RESECT(8); SAFE(9); Senft et al.(10); ANOCEF(17); ReSurge (NCT02394626); FUTURE-GB(11); G-SUMIT(12), BOLD, ATLAS/NOA-29
IDEAL 2B Studies Collaborative observational cohort studies Allowing treatment effect investigation without the ethical challenges of randomization Susceptible to bias; requires strict inclusion criteria and standardized follow-up to ensure validity First stage of FUTURE-GB(11)
Modified RCTs Adjustments to traditional RCTs Addresses ethical concerns while maintaining scientific rigor May reduce internal validity or statistical power; complex to design GBM AGILE(13)
“On/Off” and Case-Matching Studies Reducing required sample size through alternating treatment conditions or use of case-matching Expands access to treatment (potential benefit) and increases study power Potential for selection bias; difficult to control for confounders N/A
Cluster randomized trials Issue groups of participants, rather than individuals, to intervention arms Enables cooperation between centers by allowing different trial sites to adhere to best practice, while addressing variations Requires larger sample sizes; risk of contamination between clusters Roder et al.(14)
Seamless Phase II/III Studies Combining safety and efficacy assessments into a single trial through streamlining trial phases Improved efficiency: faster enrollment, reducing participant numbers, while maintaining scientific rigor Complex statistical design; risk of bias if transitions are not well-controlled GBM AGILE(13)
Shared Control Arms Re-using a control group across multiple studies or trials Reducing the number of participants receiving a potentially inferior treatment Requires high degree of coordination across studies; may raise comparability concerns GBM AGILE(13), INSIGhT(15)
Window-of-Opportunity Trials Limited period of randomization Minimizing time patients are without potential treatment, enhancing patient acceptability of randomization Recruitment is time-sensitive; not feasible in rapidly progressing conditions EGFR study(16)
Adaptive Randomization Models Bayesian statistical models reassign participants in real-time according to whether treatment effect is observed Group allocation based on emerging treatment effects, improving attainment of clinical equipoise real-time, and potentially better patient outcomes Statistically complex; requires real-time data monitoring and specialized infrastructure GBM AGILE(13), INSIGhT(15)
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RCT, randomized controlled trial.

However, alternative designs are not exempt from broader limitations such as restricted generalizability, patient selection bias, and interpretational difficulty due to confounding variables. As outlined in Table 3, each design presents limitations inherent to its methods. The use of alternative designs is not methodologically superior to RCTs, which remain the gold standard for evaluating efficacy. Rather, alternative designs represent context-dependent compromises that must be transparently evaluated for scientific rigor and ethical justification. Despite presenting with methodological challenges, alternative designs represent promising practical solutions in settings where traditional RCTs are deemed infeasible due to ethical, logistical, or treatment- and population-specific constraints. Initiatives to increase awareness of these alternative designs among the neurosurgical oncology community may facilitate their utilization.

Future directions

Ethical challenges in randomization must be clearly defined to determine when an RCT is feasible or if alternatives should be explored. The IDEAL Collaboration provides valuable frameworks for ethical considerations in surgical trials, ensuring patient safety and trial integrity. For example, IDEAL suggests that the surgical learning curve that inevitably affects trial results53,54 should be addressed prior to phase 3 studies.53,55 However, no specific guidelines for neurosurgical oncology trials exist to aid clinicians in balancing innovation and standard care, addressing conflicts between extending survival and improving quality of life, or difficulties with generalization and patient recruitment.

While the development of neurosurgical oncology guidelines depends on the availability of high-quality empirical data, structured ethical and methodological frameworks—such as the 7 criteria for ethically sound research or the IDEAL recommendations—can provide essential support for trial conduct in complex or vulnerable neuro-oncological populations, such as the elderly, neurocognitive impairment, or patients with limited prognosis. These frameworks do not replace data-driven guidance but serve as a foundation for conducting research responsibly while further evidence is generated. Future guidelines should contribute to a greater understanding of how to address vulnerable neuro-oncological cohorts in surgery while facilitating trial inclusion and equitable patient selection.22 Guidelines can ensure unified and coordinated data collection across collaborative research networks, overcoming barriers to trial enrollment, such as socioeconomic and geographic disparities, or the rarity and heterogeneity of certain neuro-oncological conditions.56,57 Neurosurgical trauma research has demonstrated the immense benefits of collaborative studies supporting evidence-based guidelines.58,59 Broad collaboration, both nationally and internationally, would reinforce the generalizability of findings beyond highly specialized scenarios.

Further research should explore the motivation of neurosurgeons to recommend neurosurgical oncology patients for clinical trials and the motivation of patients to enroll. In the context of impaired decision-making capacity, surrogate decision-makers—defined as individuals legally authorized to make healthcare decisions on behalf of the patient—may play a critical role in facilitating ethical enrollment. Though underexplored in neurosurgical oncology trials, its application has shown promise in fields such as stroke research.60–64

Limitations

The heterogeneity of included study designs, populations, focus, and outcomes prevented synthesis of precise conclusions about the role of randomization. Included studies addressed our research question from different in-depth angles, rendering the number of articles focused on any specific dimension small. The limited literature on the topic, together with its broad nature, prevented us from performing a systematic review or meta-analysis and drawing subsequent statistical conclusions. Nonetheless, this scoping review provides a comprehensive analysis of ethical considerations in randomization for clinical trials in neurosurgical oncology in a methodologically rigorous, reproducible, and informative manner.

Conclusions

Conducting surgical RCTs in the field of neuro-oncology presents significant ethical challenges, resulting from issues inherent to surgical randomization and external factors related to the study objective and treatment population, such as vulnerability and generalizability. The utility of trial results from how they are conducted and their applicability to the study population. Population-specific adaptation of trial design can serve as an adaptive tool to ensure trials meet the requirements of ethically sound research. Experts must address prevailing ethical issues and re-evaluate existing frameworks, paving the way for the advancement of robust guidelines for neurosurgical oncology trials considering ethics and methodological design considerations.

Contributor Information

Nathan A Shlobin, Department of Neurosurgery, Neurological Institute of New York, Columbia University Irving Medical Center, New York, New York, USA.

Mira C Hasner, Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, The Netherlands; Department of Neurosurgery, Leiden University Medical Center, Leiden, The Netherlands.

Philipp Karschnia, Department of Neurosurgery, Ludwig-Maximilians-University School of Medicine, Munich, Germany; Department of Neurosurgery, Uniklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.

Georg Widhalm, Department of Neurosurgery, Medical University of Vienna, Austria.

George E D Petrescu, Department of Neurosurgery, Bagdasar-Arseni Clinical Emergency Hospital, Bucharest, Romania; Department of Neurosurgery, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania.

Philippe Schucht, Department of Neurosurgery, Bern University Hospital, University of Bern, Bern, Switzerland.

Thiebaud Picart, Department of Neurosurgery, Hospices Civils of Lyon, Lyon, France; Université Claude Bernard Lyon 1, Villeurbanne, France - Cancer Research Centre of Lyon (CRCL) INSERM 1052, CNRS 5286, Lyon, France.

Marian C Neidert, Department of Neurosurgery, Cantonal Hospital St.Gallen, St. Gallen, Switzerland.

Jens Gempt, Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Rachel Grossman, Brain Tumor Center, Department of Neurosurgery, Rambam Health Care Campus, Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel.

Asgeir S Jakola, Department of Neurosurgery, Sahlgrenska University Hospital, Gothenburg, Sweden.

Michael D Jenkinson, Department of Neurosurgery, The Walton Centre NHS Foundation Trust, Liverpool, UK.

Roland Goldbrunner, Center of Neurosurgery, Department of General Neurosurgery, University of Cologne, Cologne, Germany.

Michael Weller, Department of Neurology, University Hospital and University of Zurich, Zurich, Switzerland.

Johnny Duerinck, Department of Neurosurgery, Universitair Ziekenhuis Brussel, Brussels, Belgium.

Marike L D Broekman, Department of Neurosurgery, Haaglanden Medical Center, The Hague, The Netherlands; Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, The Netherlands; Department of Neurosurgery, Leiden University Medical Center, Leiden, The Netherlands.

Funding

No funding was received.

Conflict of interest statement

MW has received research grants from Novartis, Quercis, and Versameb, and honoraria for lectures or advisory board participation or consulting from Anheart, Bayer, Curevac, Medac, Neurosense, Novartis, Novocure, Orbus, Pfizer, Philogen, Roche, and Servier. The other authors have no conflicts of interest to disclose.

Authorship statement

N.A.S., M.C.H., and M.L.D.B. conceptualized the study, searched databases, analyzed data, and wrote the initial manuscript draft. P.K., G.W., G.E.D.P., P.S., T.P., M.C.N., J.G., R.G., A.S.J., M.D.J., R.G., M.W., and J.D. analyzed data, wrote the initial manuscript draft, and provided project supervision. All authors read and approved the final version of the manuscript.

Data availability

All data analyzed in his study are available in the manuscript text and tables.

Ethics statement

Institutional review board approval was neither required nor sought as no human or animal subjects data were collected.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

All data analyzed in his study are available in the manuscript text and tables.

Articles from Neuro-Oncology Practice are provided here courtesy of Oxford University Press

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