Is there an optimal time to administer postoperative stereotactic radiosurgery in patients with brain metastases? A systematic review of the literature and meta-analysis

1 INTRODUCTION

Metastatic brain cancer (MBC) is the most common form of intracranial malignancy.¹ MBC affects 20 to 40% of metastatic cancer patients and is associated with poor prognosis despite the advent of various adjuvant therapies.² Current treatment options include whole-brain radiotherapy (WBRT), surgical resection, stereotactic radiosurgery (SRS), and systemic therapy. These modalities can be amalgamated in different combinations and demonstrate varying efficacy based on patient-specific factors such as treatment goals, intracranial tumor burden, and the molecular characteristics of the primary neoplasm.^{3, 4}

WBRT was once considered the gold standard for treating MBC after complete resection, offering symptom relief, improved local tumor control, and prevention of central nervous system (CNS) recurrence.^5-7 However, irreversible cognitive decline as a sequela of WBRT necessitated the development of additional radiation techniques such as SRS, a non-invasive ablative technique using a three-dimensional coordinate system to improve the precision of radiation delivery and minimize neurotoxicity.^{8, 9} The role of SRS in MBC treatment is well-established in the current literature supported by evidence of improved neurocognitive function and equivalent 1-year local control rates compared to postoperative WBRT.^{1, 10-12}

While SRS dosimetric parameters continue to be refined, the impact of its timing on therapeutic efficacy and patient outcomes remains undetermined. It has been hypothesized that hypoxia within the tumor microenvironment may attenuate the lethality of high-dose radiation and decrease its anticancer efficacy when employed closer to the time of surgery.¹³ On the other hand, increased time from surgery to SRS during which viable malignant cells could begin to proliferate and spread could contribute to local and regional failure. In practice, SRS timing ultimately varies based on numerous clinical, pathophysiologic, and socioeconomic factors, thereby leading to a lack of consensus among clinicians and rendering optimal radiosurgery timing unknown.^{14, 15}

We present a systematic review and meta-analysis of the literature evaluating the relationship of time to SRS after neurosurgical resection of MBC to delineate potential effects on oncologic outcomes and to further explore the variety of clinical and pathophysiologic factors which may contribute to adjuvant treatment efficacy.

2 MATERIALS AND METHODS

3 RESULTS

3.1 Systematic literature review

A total of 579 studies were screened from which 22 articles published between 2008 to 2022 met inclusion criteria for analysis (Figure 1). Studies were primarily excluded for inadequate sample size, inappropriate patient population, or unreported SRS timing. Aggregate values for each study variable are reported in Table 1 while individual data for every included article is listed in Suppl. Figure S1.

TABLE 1. The minimum, maximum, and average values for each study variable extracted from the included articles as well as the total number of articles that reliably reported each value.

Study Variable	Minimum Value	Maximum Value	Mean Value	Number of Reports (%)
Patient sample size	21	176	109	22 (100%)
Median age (years)	55	67	61	18 (81.8%)
Female sex (%)	38	76	57	19 (86.4%)
Low disease severity (%)	16.6	69	42.8	8 (36.4%)
Breast cancer primary neoplasm (%)	3.5	36	16.3	21 (95.4%)
Single intracranial metastasis (%)	0	100	68.1	17 (77.3%)
Infratentorial lesions treated (%)	8	33.3	20.7	9 (40.9%)
Gross total resection (%)	68	100	84	16 (72.7%)
Median time to SRS (days)	14.5	41	27.8	17 (77.3%)
Median SRS dose (Gy)	9	30	19.5	14 (63.6%)
Median treatment cavity volume (mL)	3.9	27.2	15.5	14 (63.6%)
Median overall survival (months)	10	20.2	15.1	18 (81.8%)
Local failure rate (%)	0	26	13	20 (90.9%)
Regional failure rate (%)	21	72	46.5	16 (72.7%)
Surgical cavity radionecrosis (%)	0	27	13.5	18 (81.8%)

3.6 Meta-regression

Median timing to SRS did not significantly correlate with percent females, percent GTR, or percent infratentorial lesions. There was a borderline correlation between average age and time to SRS, with older patients undergoing SRS at increased time intervals after surgery (R² = 0.2, p = 0.07). A similar correlation was found between SRS timing and percent of patients with low disease severity, in which patient cohorts with perceived lower risk underwent SRS treatment at a comparatively delayed time interval (R² = 0.7, p = 0.08).

Linear regression yielded a significant negative study-level correlation between median time to SRS and percent regional failure (p = 0.04, R² = 0.3). After inclusion of female percentage in the meta-regression model, the significance became borderline (p = 0.05), while the effect of female sex percentage on regional failure rate remained significant (p = 0.01). Additional variables tested, including percent of breast cancer, infratentorial disease, percent GTR, percent low disease severity, percent single intracranial metastasis, and median age, did not impact the relationship between median time to SRS and regional failure rate. There was no association between median time to SRS and median OS (p = 0.5, R² = 0.03) nor percent local failure (p = 0.2, R² = 0.1) (Figure 2).

4 DISCUSSION

With the rise of postoperative SRS use in the treatment of MBC, optimization of its workflow may maximize its known benefit to neurologic function and local tumor control.^{1, 10-12, 14, 21, 22} Studies have attempted to explore the impact of SRS timing after neurosurgical resection on clinical outcomes; however, results are mixed.^{10, 23, 24} In this study, we conducted a systematic review and meta-analysis of the literature to evaluate the relationship between postoperative SRS timing and oncologic outcomes in MBC patients.

The median postoperative SRS timing in our analysis ranged from two to six weeks.^{14, 25} Variables influencing the timing for postoperative SRS are multifactorial including socioeconomic, clinical, and logistical components. Across the articles included in our study, a longer time from surgery to SRS seemed to be associated with older age and lower-risk status cohorts. A possible explanation for these findings could be increased surgical recovery times in older patients, resulting in a delayed evaluation for adjuvant radiotherapy and oncological outpatient follow-up.²⁶ Furthermore, studies with a higher percentage of low-risk patients may represent cohorts with a favorable prognosis, which may decrease the urgency for immediate initiation of radiosurgery.²⁷ Lastly, it is possible that institutions whose populations are older and lower risk may have other systemic reasons for doing SRS later. Relevant socioeconomic and logistical variables were not analyzed in relation to SRS timing in the included articles. Similarly, clinical variables like the incidence of complications related to neurosurgical resection and length of stay (LOS) were scarcely mentioned. Neurosurgical complications, which impact LOS and a patient's ability to undergo adjuvant therapy were documented in only three of the 22 articles evaluated. Of note, no articles reported incidence of wound dehiscence or surgical site infection. Since the majority of studies did not comment on complication incidence, its impact on the timing of postoperative SRS cannot be assessed (Suppl. Figure S2).^{14, 28} Finally, one group described the exclusion of a patient from their study as a result of missing the 30-day SRS window due to surgical complications, also highlighting a need to understand and include patients who never make it to SRS.^{10, 14, 29}

Additional factors yielding delays in postoperative SRS, such as access to transportation, have been previously discussed in the literature but not systematically studied in terms of oncologic outcomes.³⁰ A study by O'Brien et al. found that logistical factors accounted for 33% of the delays in SRS treatment, while management and treatment of systemic disease and comorbidities accounted for 22.6% and 13.0% of the delays, respectively.¹⁵ Within their cohort, 12.6% of patients never received SRS despite standardized referral practices. Similarly, another group noted that rapid CNS progression, uncontrolled systemic disease requiring prolonged hospitalization, and loss of follow-up resulted in 20% of their cohort not receiving adjuvant SRS therapy.³¹ Future articles should include these variables and document patients who do not have SRS to better understand how they impact healthcare processes, delivery of treatment, and survival outcomes.

Our analysis did not show a significant relationship between SRS timing and median OS. Patient survival is mediated through a variety of oncologic variables including but not limited to primary cancer histology, extracranial disease status, local and regional failure, and treatment tolerance. Indeed, postoperative radiation has not been shown to improve survival, therefore, it is not surprising that time to SRS does not seem to relate to survival at an institutional level.¹⁵

Our results showed that the median time to postoperative SRS did not significantly correlate with local failure rates, similar to Brennan et al,³¹ yet contrary to findings from other individual cohort studies.¹⁵ One study suggested that administering SRS within three weeks of surgery was important to minimize the risk of local tumor recurrence independent of variables, such as extent of tumor resection, primary cancer histology, or the size of the surgical cavity to be treated.²⁴ Conversely, another study suggested that delaying postoperative SRS for more than 3–4 weeks after the initial resection could maximize spontaneous tumor bed ischemia and reduce the volume of radiation needed for effective treatment.^{10, 23} The lack of significance in the meta-analysis presented herein is likely attributed to the significant level of heterogeneity in study methodology, limited range of reported local control rates, inability to account for length of follow-up, as well as cohort demographics. Moreover, our meta-analysis investigated this relationship at an institutional level, in contrast to the analyses performed at an individual level seen in these articles. At present, the temporal relationship between adjuvant SRS timing and local failure remains unclear.

Regarding regional failure rates, this study showed that delayed administration of postoperative SRS was significantly associated with decreased regional failure rates. Selection bias in the form of confounding by the severity of the patient's disease is possible as lower disease severity was associated with a longer time to SRS, however, when adjusting for other markers of severity there were no effects on this relationship. We also cannot exclude other forms of selection bias or institution-level correlations between resources or care coordination and clinical variables. Although causation cannot be implied from our data, one hypothesis is that providers may prioritize control of extracranial disease when intracranial risk is low while waiting for patients to fully recover from surgery prior to undergoing SRS, though our data cannot test this hypothesis.²⁴ The presence of active extracranial disease in the patient cohort was evident in several articles, with some attributing its presence as the reason for delayed SRS administration and others noting its significant negative impact on overall survival.^{23, 32, 33} Ongoing adequate management of a patient's systemic disease in the immediate postoperative period may be important to lower the risk of developing new CNS metastases and concomitantly benefit existing intracranial malignancy depending on the histopathologic subtype and the systemic treatment being used.^{34, 35} Future studies should include information on the systemic therapies used in parallel during this course.

Our study also investigated the potential adverse effects of postoperative SRS to determine if variation in timing also impacted their incidence, particularly radionecrosis. Findings were largely nonexistent with no wound-related complications described. Likewise, nine studies in total reported no evidence of radionecrosis, conflicting with previous estimates in the literature approaching up to 30%.^36-40 Potential explanations for these results include limited lengths of follow-up or the methods used to confirm radionecrosis, including histopathologic analysis via tissue biopsy versus magnetic resonance imaging (MRI). For example, the diagnostic accuracy of radionecrosis is limited by the difficulty in distinguishing it from tumor recurrence using imaging alone since both radionecrosis and tumor recurrence can present as edematous ring-enhancing lesions.^{41, 42} Finally, associations between the incidence of radionecrosis, median time to SRS, radiation dose, and location of the metastatic tumor were not investigated in the studies. Standardizing the diagnostic methods used to confirm and report radionecrosis will in turn improve our understanding of the impact of these various factors, including the timing of adjuvant SRS treatment, on its development.

The limitations of our study stem from its cross-sectional design and meta-analysis. Although many potential factors influencing postoperative SRS timing were not formally documented in the evaluated studies, the heterogeneity in their methodology, patient population, and primary outcomes possess a greater barrier to research on this topic (Suppl Figure S3)(Suppl Figure S4). Important variables known to contribute to SRS-related treatment outcomes, including number of metastases, RPA class, and primary malignancy, differed significantly between the studies.²¹ Additionally, the primary clinical questions and aims of each article differed, leading to significant variations in overall study design.^{27, 43, 44} Finally, this meta-analysis evaluated relationships at an institutional level, which may differ from correlations at the individual patient's level. The small number of studies and the heterogeneity amongst them reduces the power of our analyses. Due to significant publication bias, our literature search may not fully encompass the full spectrum of postoperative SRS timing, possibly not accounting for smaller studies with shorter times to SRS. Our analysis supports the need for larger controlled cross-institutional studies with the ability to accurately account for confounders, identify patterns of treatment-related adverse effects, stratify patients based on postoperative SRS timing, and comprehensively report the socioeconomic, clinical, and logistical factors that influence timing of SRS administration.

5 CONCLUSION

Postoperative SRS is a safe and effective treatment for patients with metastatic brain cancer most often employed between two to six weeks after tumor resection. This meta-analysis showed no correlation between median postoperative SRS timing and local failure rate and median OS. Our conclusions are limited by significant variability in the study population and publication methodology. Therefore, further research through larger-scale studies with consistent methodologies is necessary to better understand these potential relationships, optimize radiosurgery workflow, and improve outcomes in this patient population.

AUTHOR CONTRIBUTIONS

A.N., D.D., K.C., S.K., A.C., and M.Z., contributed to the study's conception and design. Material preparation, data collection, and analysis were performed by A.N., D.D., and A.C. The first draft of the manuscript was written by A.N., D.D., while K.C., S.K., A.C., and M.Z. commented on previous versions of the manuscript. A.N., D.D., K.C., S.K., A.C., and M.Z., read and approved the final manuscript. M.Z. and A.C. supervised the study.

CONFLICT OF INTEREST STATEMENT

The authors of the enclosed manuscript have no relevant financial or non-financial interests to disclose.

FUNDING INFORMATION

Not applicable.

ETHICAL APPROVAL

Not applicable.