The adrenal glands are a common site of metastasis., accounting for up to 38% of metastastatic cancers (1), with melanomas (50%), lung and breast cancers (30-40%), and renal and gastrointestinal tumors (10-20%) (2) being commonly affected due to the adrenal glands’ rich blood supply (3). Advanced imaging and close follow-up programs for cancer patients have led to a rise in their detection, typically at the oligometastatic stage. Targeted local therapies are gaining popularity as ablative therapy may improve outcomes in patients with limited systemic disease burden (1, 2). A paired analysis of 62 patients with isolated AM found that SBRT and laparoscopic adrenalectomy had similar outcomes and survival rates (4), but complications occurred in 37.9% of patients, including ileus or gastroparesis, wound problems, pneumonia, and heart arrhythmia (5). Stereotactic body radiation therapy (SBRT) enables conformal delivery of ablative radiation doses using single or a small number of fractions, resulting in a more effective radio biologic dose (6). SBRT has become an important treatment option for adrenal metastases, with its low toxicity and ability to maintain adrenal function.

However, there are currently no specific clinical guidelines established for SBRT in AM. This has resulted in considerable diversity in prescription doses and fractionation plans in clinical settings (7), with notable fluctuations in 1-year and 2-year LC rates, spanning from 44% to 100% and 27% to 100%, respectively (8) Consequently, it is critical to investigate risk factors and develop reliable models to guide clinical dose selection.

We conducted a systematic search for relevant studies in PubMed, Embase, and Web of Science, including those published up to July 2022 and updating the search until September 22, 2022. Thirty-three studies published between 2009 and 2022 were included, covering 1483 patients with 1660 lesions (3, 7, 9–38). The screening flow diagram was shown in Supplementary Figure A and clinicopathologic characteristics in Supplementary Table A . The search query used was “stereotactic OR radiosurgery OR sbrt OR sabr OR knife) AND (adrenal/exp OR adrenal) AND (metastasis/exp OR metastasis OR metastases/exp OR metastases OR metastatic)” (39). We excluded studies that did not report treatment outcomes or toxicity data specific to SBRT for AM, studies that did not grade toxicities according to Common Terminology Criteria for Adverse Events (CTCAE) criteria or define radiological responses according to the Response Evaluation Criteria in Solid Tumors criteria (RECIST) criteria, studies without BED₁₀ information, redundant data or those reporting on fewer than 5 patients, or non-English reports were excluded. We followed PRISMA guidelines. Survival outcomes were calculated per patient, while the LC rate was calculated per metastatic lesion. Some outcome values were obtained from local control probability curves using Engauge Digitizer. SBRT was defined as the delivery of higher fractional doses of radiation than conventional fractionation (>1.8-2.5Gy) in a relatively small number of fractions (39). Local control was defined as the absence of progression at the treatment site. Oligometastatic disease defined as limited metastatic disease burden with 5 or fewer lesions in 2 or fewer organ sites. Synchronous metastases were defined as those present at the time of first diagnosis or appearing within 6 months. Since some criteria differed between studies, we performed simple calculations, such as calibrating technology adoption rates based on patients rather than lesions in some studies (7, 32). Biological effective doses were calculated by following quation:

where d is the single radiation dose, n is the number of fractions, and we picked up α/β =10Gy.

A pooled analysis based on maximum likelihood estimation was used to determine weighted study level rates of 1,2-year LC and 1,2-year OS, and subgroup analysis and meta-regression were conducted to explore possible sources of heterogeneity among study results. Qm was used to assess the degree of heterogeneity (variation) among the effect sizes of individual studies. Significant risk factors identified through meta-regression testing also need to undergo collinearity detection. We reported the total number of adverse events rather than estimating a pooled statistic because the reported rates of grade 3+ toxicity were uniformly low and frequently zero.

Out of 915 records, we included 33 studies published between 2009 and 2022 that reported outcomes for 1483 patients with 1660 lesions of AM. The median follow-up was 13.4 months, ranging from 0 to 124 months, and the median OS was 19 months, ranging from 0.4 to 171 months. The median total dose was 36Gy(10-70Gy) and the median number of fraction was 4.5(1-18). The median dose per fraction was 7.5Gy, ranging from 2 to 30Gy, and the median BED10 was 71.4Gy, ranging from 20 to 180Gy. Among the patients, 61% had were primary lung cancer patients, and 91% were oligometastatic or oligoprogressive patients. Ninety-four percentage of the studies included data on the method of diagnosis, and only three studies reported biopsy tissue confirmation along with fiducial placement. Out of 1483 patients, only 19 (1.3%) patients reported grade3+ toxicity response, and out of 1401 patients, 22 patients (1.6%) experienced adrenal insufficiency. For more detailed information, please refer to Table A in the Supplement Tables . The pooled 1- and 2- year LC were 82% (95% CI, 76%-87%) and 63% (95% CI, 54%-72%), respectively, and the pooled 1- and 2- year OS were 67% (95%CI, 62%-73%) and 47% (95%CI, 40%-53%), respectively. The forest plots, funnel plots and sensitivity analysis were shown in Figures B–D in the Supplement Figures .

Delivery of high-dose on adrenal gland can be challenging due to the proximity of risk organs such as the duodenum, small intestine, and stomach, with dose limit violations potentially leading to life-threatening complications (40). In clinical practice, compromises on target doses are necessary (4, 8). Moreover, the overuse of radiation can trigger the expression of certain proteins, such as Transforming Growth Factor (TGF), Indoleamine-pyrrole 2,3-dioxygenase (IDO), and Programmed cell Death-Ligand 1 (PD-L1), which contribute to an increase in immune-suppressive cells like Tregs and tumor-associated macrophages (TAMs) (41), and have harmful effects on the immune system’s ability to fight cancer cells. Thus, seeking a dose scheme under 100Gy of BED₁₀ not only helps to protect the surrounding organs at risk, but also helps to weaken the local immunosuppression around the tumor.

Our study underscores the importance of fractionated doses and emphasizes that fractionated doses should not be less than 9 Gy. When it is not feasible to achieve the currently recommended BED10 ≥ 100 Gy total dose, our study offers a solution by increasing the fractionated dose. This finding aligns with experimental data (42–44), as doses greater than 8-10 Gy, as opposed to doses greater than 5 Gy, can result in rapid endothelial cell apoptosis, leading to extensive tumor cell death and severe hypoxia in the microenvironment. Furthermore, the release of tumor antigens during the death or dying process of tumor cells post high fractionated radiation can trigger an anti-tumor immune response within weeks to months, contributing to the formation of a local immune environment (45, 46). There is evidence that in animal experiments, a dose of 8-10 Gy is optimal, as fractionated radiation at 8 Gy, combined with CTLA-4 inhibitors, can induce a distant effect (47).

Our research demonstrates that the utilization of tracking technology not only contributes to extending the survival of patients with AM but is also highly safe. Real-time monitoring and tracking of tumor location is an emerging technology to enhance the precision of tumor radiotherapy (48). This technology allows for high-dose, high-accuracy irradiation of the tumor, improving treatment effectiveness while avoiding “off-target” effects in the target area, and reducing adverse effects on surrounding tissues (48, 49). A study published in the journal Nature Cancer suggests that damage to tissues caused by “off-target” radiotherapy can locally activate neutrophils in the normal repair process and Notch signal transduction, which can promote cancer metastasis and reduce overall survival (50). For under-irradiated tumors cells, insufficient radiation fails to kill them; instead, it enhances its malignancy and promotes invasion and metastasis (51, 52).

Therefore, the application of real-time tracking technology is essential, especially for patients with AM. We found that 91% of AM patients fall within the current definition of oligometastasis. Multiple studies have shown that aggressive treatment in oligometastatic patients can significantly extend survival (53–55). However, regrettably, the use rate of tracking technology is only 19% (257/1332) and the importance of tracking technology urgently needs to be widely promoted. Of course, we also need to be vigilant about selection bias. Because this portion of patients in the high fiducial adoption group may also have better medical support, which could potentially influence the overall survival outcome. Nevertheless, we cannot deny the importance of adopting tracking radiation therapy, and we hope that prospective studies in the future will confirm our findings.

We are the first to propose a study on the focus of fractional dose and tracking technology in the treatment of AM using SBRT. William C. Chen et al (39) collected 39 studies between 2009 and 2019 to perform first meta-analyze on AM by SBRT. They only analyzed the relationship between the total dose (BED10) and local control, as well as overall survival, and reached the conclusion that dose escalation contributes to local control. They did not analyze and find the significance of fractionation dose and tracking techniques, perhaps due to the inclusion of a large number of abstracts with insufficient information in their study. To extract more data and ensure data accuracy, we excluded all studies that had only abstracts and lacked full texts. Furthermore, due to the recent advancements in tracking technology and the development of imaging techniques, many new articles (14/out of 33) on SBRT treatment for AM have emerged. Therefore, there is an urgent need for updated meta-analyses in this regard.

Our study has some limitations that need to be acknowledged. The inconsistencies in radiation techniques and dosimetry, and the inherent biological inaccuracies in calculating BED by linear-quadratic (LQ) formulas, mean that the reported doses are only informative and should be carefully considered. As our study is a retrospective analysis, it cannot establish causal relationships, and more prospective studies are needed to verify our findings. The results of meta model-based estimates should be interpreted with caution, given the heterogeneity of tumor control estimates extracted from the literature and the variability of diametric data reporting, as well as the definitions and statistical methods used to report tumor control. Despite our efforts to collect data of the same quality, there were still some differences in detail.

SBRT is a safe technique. Constrained by organs at risk, the clinical dose for treating AM often falls within the range of 40-80 Gy, especially in centers with low tracking adoption rates. But we recommend that the minimum dose per fraction should be set around 9 Gy to ensure treatment efficacy.Additionally, the use of tracking techniques may improve the survival rates of advanced AM patients and is strongly recommended. Prospective studies are needed to validate these discoveries.

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding author.

XL had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: KK. Acquisition, analysis, or interpretation of data: all authors. Drafting of the manuscript: all authors. Critical revision of the manuscript for important intellectual content: KK and RK. Statistical analysis: XL. Obtained funding: CP. Administrative, technical, or material support: KK, CP. Supervision: KK, CP, RK. All authors contributed to the article and approved the submitted version.