The Role of CyberKnife Stereotactic Radiosurgery in Recurrent Cranial Medulloblastomas across Pediatric and Adult Populations

1. Introduction

First described in 1925, medulloblastoma remains as a significant malignant brain neoplasm predominantly affecting the pediatric population [1]. Manifesting with a peak age of diagnosis between 6 to 8 years, the traditional therapeutic triad of surgery, chemotherapy (CT) and radiation therapy (RT) has been the mainstay[2,3]. Notably, recent decades have ushered substantial transformations in therapeutic strategies, marked by an enhanced understanding of molecular subgroups influencing both prognosis and treatment modalities [4]. Despite these strides, the absence of clear guidelines for managing recurrent cases underscores the persistent clinical challenges, especially given the aggressive nature of recurrent medulloblastoma [5].

The intricate interplay between the infiltrative nature of medulloblastoma and the intricacies of neural architecture demands precise and efficacious therapeutic strategies [6]. Within this context, stereotactic radiosurgery (SRS) has emerged as a focal point in the management of recurrent medulloblastoma [7]. Leveraging targeted ionizing radiation, SRS strategically engages the biological vulnerabilities of the pathology. Bolstered by advancements in radiological imaging, radiation delivery platforms, and an evolving comprehension of radiobiology, SRS has assumed a pivotal role in combating this challenging adversary[8,9].

In our study, we demonstrate the efficacy and safety of SRS over the long term, specifically for both pediatric and adult patients grappling with the formidable burden of recurrent medulloblastoma. Situated within a single institution, our investigation uniquely integrates clinical expertise with research acumen, providing a nuanced perspective on the multifaceted dimensions of SRS application in the context of the recurrent nature of medulloblastoma.

2. Methods

Patient Selection and Characteristics

Between 1998 and 2023, we identified and treated 15 cases of recurrent medulloblastomas in 10 patients at Stanford University Medical Center using CyberKnife SRS. The selection criteria included a minimum follow-up period of 6 months. Clinical data were stored in a database approved by the Institutional Review Board (IRB) and complied with the Helsinki Declaration. The detailed overview of the patient demographics is presented in Table 1.

The study cohort comprised 8 (80%) pediatric patients (ages 3-18) and 2 (20%) adult patients (ages 19-75). The median age at the time of SRS was 13 years, with the pediatric group having a median age of 12 years (range: 9-16) and the adult group with a median age of 27 years (range: 25-29). Nine (90%) patients underwent prior surgery prior to SRS, with histological confirmation of WHO grade IV recurrent medulloblastomas. Additionally, one (10%) adult patient received RT as primary treatment based on radiographic diagnosis. Symptoms were correlated with lesion location and included headaches, ataxia, nausea, vomiting, seizures, visual impairment, and motor impairment (Table 1).

Tumor Characteristics

The overall study included 10 patients with 15 recurrent cranial medulloblastomas. The median tumor volume was 1.9 cc (mean: 2.7; range: 0.02-8.7); with the pediatric group having a median of 1.9 cc (range: 0.02-8.7) and the adult group having 1.5 cc (range: 0.5-2.5). Most lesions (86.7%) occurred in pediatric patients, primarily located in the cerebellum (n = 5, 33.3%), followed by ventricular (n=2, 13.3%), parietal (n=2, 13.3%), and frontal (n=2, 13.3%) regions (Table 1).

Treatment

Cranial recurrent medulloblastomas were treated with CyberKnife SRS (Accuray, Inc., Sunnyvale, CA) utilizing the established method previously outlined by Shi et al. [10]. The median time between initial diagnosis and SRS was 30 months (range: 12-108); 39 months (range: 12-108) in the pediatric group and 24.5 months (range: 24-25) in the adult group. SRS was administered with a median single-fraction equivalent dose (SFED) of 18 Gy to the 75% median isodose line (range: 65-81). Marginal dose, maximum dose, isodose line, and the number of fractions did not significantly differ between cohorts (Table 2).

Biologically Effective Dose (BED), Single-Fraction Equivalent Dose (SFED), and Equivalent Total Doses in 2-Gy Fractions (EQD2)

The biologically effective dose (BED) was calculated using the linear-quadratic (LQ) model with a α/β ratio of 3 Gy[11,12]. The BED was converted to SFED and the equivalent total doses in 2-Gy fractions (EQD2) using LQ model [13]. Median BED, SFED, and EQD2 for the entire cohort were 126 Gy (range: 66.7-153.3), 18 Gy (range: 12.7-20), and 75.6 Gy (range: 40-92), respectively, with no significant differences observed between groups (Table 2).

Follow-up

Patients underwent clinical evaluation and MRI follow-up semi-annually for the first two years after SRS, followed by annual assessments. Tumor volume was measured in axial, sagittal, and coronal planes and analyzed using Kaplan-Meier analysis. Graphical representations were generated using standard statistical software (IBM SPSS Statistics 29.0, Chicago, IL).

3. Results:

Patient Demographics and Characteristics

Following the exclusion of patients lost to follow-up, 15 lesions in 10 patients were included in the study. The cohort consisted of 8 (80%) were pediatric and 2 (20%) adult patients, while 5 (50%) patients succumbed during the evaluation period. The median follow-up after SRS was 39 months (range: 6-78) (Table 2).

Local Tumor Control

Among the 15 recurrent medulloblastomas, 8 (53.3%) demonstrated progression, 2 (13.3%) exhibited radiographic regression, and 5 (33.3%) remained stable. LTC rates for all medulloblastomas were 86%, 65%, and 31% at 1, 3, and 5 years, with a higher rate observed in pediatric patients (67%) at 3 years compared to the adult cohort (50%) (Table 3, Figure 1A).

Analysis of LTC rates revealed interesting patterns related to the location of tumors. Cerebellar lesions demonstrated a favorable response with a 78% LTC rate at 3 years compared to 50% for ventricular lesions. Furthermore LTC rates correlated with the number of prior surgeries, with a higher rate in patients who had undergone a single surgery (75%) compared to those with multiple surgeries (66.7%) (Table 1 and Table 3).

Patient Survival

OS rates for all patients were 90%, 70%, and 35% at 1, 3, and 5 years, respectively. Pediatric patients demonstrated higher rates of overall survival (75%) compared to adult patients (50%) at 3 years (Table 3, Figure 1B).

Survival outcomes were also influenced by clinical presentation. Asymptomatic patients exhibited a 100% OS rate at 3 years, while symptomatic patients showed varied rates based on the location of the tumor (Table 1 and Table 3).

Progression-Free Survival

PFS rates were 90%, 58%, and 29% for all patients at 1, 3, and 5 years, with a higher rate observed in the pediatric cohort at 3 years (60%) (Table 3, Figure 1C).

PFS was notably influenced by the age at treatment, with pediatric patients experiencing a 60% PFS rate at 3 years compared to 50% in adults. Additionally, a positive correlation was observed between PFS and target tumor volume, with larger volumes exhibiting a slightly higher PFS rate (Table 2 and Table 3).

Symptomatic Outcome

In the entire cohort, one (10%) pediatric patient was asymptomatic, allowing the evaluation of symptomatic outcomes for 9 (90%) patients with 14 (93.3%) symptomatic medulloblastomas. Overall, 7 (77.8%) patients demonstrated symptomatic improvements following SRS (Table 3). Notably, symptomatic improvement was more significant in the pediatric cohort (75%) compared to the adult cohort (50%) (p=0.05). The improvements were observed in headaches, nausea, vomiting, ataxia, and visual impairment. However, one (12.5%) pediatric patient and one (50%) adult patient experienced worsening headaches, and one (50%) adult patient presented with new symptoms, including dizziness and vomiting after treatment with SRS (Table 3).

Symptomatic outcomes were associated with the location of tumors, with cerebellar lesions showing the highest rate of improvement (80%). Furthermore, improvements in symptoms were more pronounced in cases with a single prior surgery compared to multiple surgeries (81.3% vs. 57.1%) (Table 1, Table 2 and Table 3).

Adverse Radiation Effect (ARE)

Among the entire cohort, 2 (20%) pediatric patients experienced radiation-induced edema and 2 (20%) adult patients confirmed radiation necrosis. Patients who experienced ARE had similar dose parameters as the overall cohort, highlighting the need for further investigation into individual susceptibility factors.

4. Discussion

Our investigation into the outcomes of SRS for recurrent cranial medulloblastomas presents a thorough analysis of treatment efficacy and patient management (Figure 2). In light of the identified variations in treatment outcomes between pediatric and adult patients, a nuanced customization of treatment strategies emerges as imperative. This divergence may stem from enhanced central nervous system (CNS) plasticity in pediatric patients or the presence of less aggressive tumor types [14]. By integrating demographic, clinical, and treatment factors, our study provides a nuanced understanding of the intricate landscape associated with recurrent medulloblastomas.

Local Tumor Control

The observed LTC rates, notably the substantial 67% rate at 3 years in the pediatric cohort, emphasize the potential efficacy of SRS in managing recurrent medulloblastomas. Our findings align with existing literature, underscoring the significance of precision in targeting specific tumor locations, particularly cerebellar lesions, to optimize treatment outcomes[7,15,16,17,18].

Pediatric patients, who constitute a majority in our cohort, exhibit a higher prevalence of cerebellar lesions, possibly contributing to the enhanced LTC rates observed in this subgroup (Table 1). Conversely, the prevalence of multiple prior surgeries in the adult cohort may be linked to comparatively lower LTC rates, suggesting a potential association between prior surgical intervention and LTC outcomes[19,20,21]. Further exploration of associations between the number of fractions, BED, and LTC rates, considering factors such as age and tumor location, could enhance our understanding of the interplay influencing LTC outcomes.

Patient Survival and Progression-Free Survival

The OS rates of 90%, 70%, and 35% at 1, 3, and 5 years underscore the potential long-term benefits of SRS in managing recurrent cranial medulloblastomas, especially given their aggressive nature [22]. The discernibly elevated survival rates in pediatric patients compared to their adult counterparts emphasize age as a pertinent prognostic factor[23,24]. The prevalence of multiple prior surgeries in the adult cohort may contribute to the lower OS rates, emphasizing the impact of prior treatment history on long-term survival outcomes [25]. Shorter intervals between diagnosis and SRS may be associated with more favorable outcomes, suggesting that prompt initiation of SRS after diagnosis could contribute to improved survival rates. Smaller tumor volumes may correlate with greater OS and PFS outcomes, highlighting the importance of accurately defining and targeting tumor boundaries during SRS [26]. Optimal margin doses contribute to improved OS and PFS, and deviations from this may impact outcomes [27]. The nuanced interplay of these factors underscores the need for personalized treatment strategies, tailoring therapeutic approaches based on individual patient characteristics to optimize treatment outcomes.

Symptomatic Outcomes

Our investigation of symptomatic outcomes post-SRS reveals notable improvements, particularly in the pediatric patient cohort. With a higher percentage experiencing SI and lower rates of SW and NS, a potential correlation between clinical response and long-term survival outcomes is suggested [28]. Pediatric patients, constituting 80% of our cohort, demonstrate a particularly encouraging trend in symptomatic outcomes[29,30]. The SI percentage of 75% in the pediatric group, compared to 50% in adults, underscores the positive impact of SRS on symptom relief in younger patients [31]. The correlation between tumor location and SI emphasizes the need for tailored treatment approaches, with targeting cerebellar lesions yielding favorable symptomatic outcomes. The influence of the number of prior surgeries on symptomatic outcomes necessitates a critical examination of the optimal timing and extent of surgical interventions in managing recurrent medulloblastomas[30,32]. While SRS contributes to SI, understanding the interplay between prior surgeries and post-SRS symptoms is crucial for refining treatment strategies [33]. Our findings suggest that a judicious approach to surgical interventions, considering factors such as timing and extent, may contribute to more favorable symptomatic outcomes in the context of recurrent medulloblastomas.

Adverse Radiation Effects

The identification of radiation-induced edema and necrosis, albeit in a subset of patients, accentuates the critical role of meticulous dose planning[29,34]. These occurrences in both pediatric and adult patients underscore the imperative for personalized treatment strategies to mitigate ARE. [1] The absence of myelopathy provides reassurance and aligns with the safety profile reported in the existing literature[35,36].

Integration with Previous Studies

Our findings harmonize with prior studies exploring the role of SRS in recurrent medulloblastomas, emphasizing the indispensability of a multidisciplinary approach in patient care[4,31]. The alignment with established literature buttresses the generalizability of our results and contributes substantially to the burgeoning body of evidence supporting the efficacy of SRS in recurrent cranial medulloblastomas.

Limitations and Future Directions

Notwithstanding the promising results, our study is not immune to limitations. The retrospective nature of the analysis and the relatively modest sample size warrant cautious interpretation. Prospective studies with larger cohorts are imperative to validate our findings. Additionally, sustained long-term follow-up is pivotal for assessing the durability of treatment responses and potential late effects. These considerations acknowledge the current limitations and provide a foundation for future research to build upon our initial insights.

5. Conclusion

Our study offers a nuanced perspective on the efficacy and safety of CyberKnife SRS in addressing recurrent cranial medulloblastomas in both pediatric and adult demographics. The infrequency of ARE accentuates the favorable safety profile associated with CyberKnife SRS, thus affirming its contributory role in optimizing treatment outcomes. The intricacies of symptomatic responses, entangled with variables such as age, tumor localization, and prior surgical interventions, underscore the imperative for individualized therapeutic strategies. Our results underscore the need for ongoing research endeavors and the development of more refined and effective treatment strategies for recurrent medulloblastomas. Given the observed disparities in treatment outcomes between pediatric and adult cohorts, a more meticulous tailoring of treatment modalities becomes crucial.