On November 5, 2024, an advanced search using the query “(stereotactic radiotherapy) AND ((non-target radiotherapy) OR (abscopal) OR (distant bystander))” was conducted on PubMed and Scopus. The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) methodology [20, 21] was employed.

Exclusion criteria:

1.

Articles not relevant to the topic (e.g., neither SBRT nor NTER, NTER following non-SBRT treatment, non-NTER evaluations after SBRT). Cases where the ablative intent was evident but the dose per fraction was clearly < 5 Gy were also excluded.

Given the expected rarity of the phenomenon, case reports and case series were included, along with studies evaluating NTER without observed events. Bibliographies of selected articles were also reviewed for additional relevant reports. No automation tools were utilized during the process.

Following the screening process, the following information was systematically extracted from each study and organized in a database: authors, country of origin, publication year, patient demographics, tumor location, study setting, and details of SRT [treatment schedule, target site(s) and number of lesions, prescribed biological effective dose in BED and EQD2, with an alpha/beta ratio of 10]. Additionally, non-targeted response measures were recorded, including the definition of responses, the number of patients evaluated, the number of abscopal events, the target sites, time to onset, and progression-free survival. Oncological treatments were categorized based on IT or targeted therapy (neoadjuvant, prior optimal or suboptimal response, concurrent therapies with details on discontinuation times, adjuvant therapies, and reported toxicities). The limitations of each study were also noted. The results were presented in two main sections: an overview and a detailed district-by-district analysis, with a focus on prospective studies. The sections included:

1.

Study characteristics.

A dedicated Discussion section was included to critically assess the findings. In addition, recommendations for standardizing reporting in future studies were provided.

The database search identified 422 articles; 20 additional reports were identified throughout a bibliographies search. After screening, 63 articles were selected for review [22–84]. The PRISMA workflow for data selection and collection is shown in Figure 2.

Figure 3 provides an overview of studies reviewed, by publication year and country source.

A significant portion of the studies (84%) was published from 2018 onwards. Over a third of the studies were conducted by researchers from the United States. Figure 4 provides an overview of the papers by study type and primary tumor examined.

Of the selected studies, 32 were case reports or case series, 18 were retrospective studies, and 13 were prospective studies. NTER was the primary endpoint in 6 studies (23%). The criteria used by the authors to define NTER, listed from most to least common, included:

1.

Any response outside the radiation field.

SRT was planned as the primary treatment in 95% of the studies reviewed. In only 5% of the cases, SRT was considered an alternative to surgery or other treatment options (3%) [40, 83], or it was the only available option after reirradiation (2%) [67]. One study explored the use of SRT in a novel neoadjuvant setting [69]. The targets for SRT were metastases, except in 7 studies [40, 41, 44, 47–49, 84], where the primary tumor was either the exclusive target or one of the irradiated targets. In 5 studies [31, 35, 39, 50, 73], G ≥ 3 toxicity attributable to IT was reported.

NTER was the primary endpoint in 8 studies (17%) [25, 28, 31, 45, 46, 54, 75, 76]. Overall, NTER was reported in 297 patients: 34 from case reports or case series, and 263 from retrospective or prospective studies (22% of 1,212 evaluable patients). Notably, in 10 studies, NTER was evaluated but no positive events were reported [26, 31, 32, 34, 41, 53, 56, 73, 77, 79]. When considering only retrospective studies, NTER occurred in 147 out of 892 evaluable patients (16.5%), while in prospective trials, NTER was observed in 116 out of 320 patients (36%). The majority of NTER cases were reported as AE, while BE were evaluated in only two studies [40, 75], with a 20% occurrence rate.

Considering cases where single patients, tumor and treatment characteristics were available, SRT was planned after a median of 12 months (range: 0–84 months) from diagnosis, following a median of 1 (range: 0–5) prior therapeutic lines. The median age of patients at the time of SRT was 61 years (range: 24–78). The median follow-up time was 15 months (range: 4.5–120 months). In approximately half of the cases, patients were receiving immune or targeted therapy at the time of SRT, and in all cases except one [40], NTER occurred after a suboptimal response to previous systemic treatment. Only 2 studies reported interruption of IT during SRT [44, 78]. The target response was complete response (CR) in 58% of cases, with the remainder showing partial response (PR).

SRT prescription doses were reported in 95% of the cases, while target volumes were described in only a few studies [22, 27, 40, 46, 82]. The median time between SRT and NTER was 3 months (range: 1–30 months). NTER involved a single site in half of the cases. In cases of AE, CR occurred in 50% of instances. When a PR was reported, the change in the abscopal response was noted in a few cases [64, 83], with a range of 18.7% to 40.9%. The EQD2 for the SRT prescription dose in patients who experienced NTER ranged from 22 Gy to 134.77 Gy, with a median of 69.75 Gy; the BED ranged from 26.4 Gy to 161.72 Gy, with a median of 83.7 Gy. In retrospective and prospective studies, the median BED ranged from 37.5 Gy to 119 Gy.

Non-targeted volumes were reported in only 2 studies [46, 82], with the doses received by non-targeted volumes documented in only 2 studies. One study reported a maximum dose of 0.4 Gy, while the other recorded a fractional dose of 1.24 Gy and a low-scatter dose of 7.6 Gy/4 fractions [83]. Detailed progression of AEs in the irradiated and non-irradiated sites was reported in a few cases [58, 64, 70, 78]. The longest reported progression-free survival after NTER was 120 months [27].

The majority of documented AE following SRT involve melanoma [22–39]. Its resistance to chemotherapy (CHT) and radiation coupled with a strong propensity for early metastasis, with a particular tropism for the brain, makes it one of the most aggressive malignancies. However, recent advances in biologic and immunologic therapies have improved the prognosis for patients with advanced-stage melanoma [85, 86]. Melanoma is highly immunogenic, and the introduction of anti-CTLA-4 and anti-PD-1 therapies has significantly enhanced treatment outcomes for advanced or metastatic cases [87].

NTER have been documented in 121 melanoma patients, including 7 cases from individual reports or case series [22, 24, 27, 29, 30, 39], and 104 cases from retrospective [23, 25, 26, 32, 34, 36–38] and prospective [28, 31, 33] studies, representing 22% of the total sample. In most of these cases, patients were receiving anti-PD-1 therapy in combination with SRT. When analyzing retrospective versus prospective studies, NTER was observed in 78 out of 399 (19.5%) and in 23 out of 71 (32.3%) respectively.

A prospective cohort study published by Roger et al. [28] in 2018 assessed the efficacy of combined 26 Gy SBRT (3–5 fractions) or SRS with PD-1 monotherapy in 25 advanced melanoma patients. For non-irradiated lesions, the response rates were 20% CR, 19% PR, 12% stable disease (SD), and 40% progression disease (PD). In a study by Trommer et al. [38], melanoma was the most common primary tumor (66.7%) among the 319 brain metastases (BM) treated with radiotherapy and anti-PD-1 therapy. Specific immune responses, including AE, pseudoprogression, or immune-related adverse effects, occurred more frequently with concurrent RT-IT and were associated with improved OS compared to non-concurrent treatments.

Funck-Brentano et al. [33] conducted a study in 2017 that evaluated the efficacy of late concurrent SRT in 133 advanced melanoma patients who had failed anti-PD-1 monotherapy. They reported an AE occurrence in 35% of cases. Similarly, a cohort of 206 melanoma patients who had received anti-PD-1 monotherapy and subsequently underwent hypofractionated radiation therapy also evaluated AE as a secondary endpoint. In this cohort, AE was observed in 31.5% of evaluable patients [36]. Although several other studies on NTER after SBRT for melanoma yielded negative results [26, 31, 32], NTER was also reported in a rare case of mucosal melanoma treated with a combination of nivolumab and the novel agent relatlimab [39]. Table 1 provides an overview of each study reviewed for melanoma tumors.

In the HN district, NTER after SBRT experience is limited to 5 patients, mostly from single cases [40–45].

Among brain primaries, a BE has been reported only for an extensive meningiomatosis after gamma knife radiosurgery in 2022 [40].

A potential AE with combination of SRT and IT for HN cancers has been firstly described by Choi et al. [41] in 2020 with 2 case series. A further experience is provided by Ito et al. [45] in a multicenter prospective observational study, in which one out of two patients with metastatic HN, evaluated for AE as primary endpoint, showed a systemic response to SBRT combined with nivolumab. NTER has been evaluated by other 2 studies [42, 43] but no events were reported.

Table 2 provides an overview of each study reviewed.

IT has not yet become a significant treatment for advanced breast cancer [88]. While no single cases have been reported, Kim and Chang’s study [46] documented an NTER effect in 25% of patients, with a median interval of 2.1 months. Of these lesions, 70% did not progress for up to one year. Multivariate logistic regression analysis revealed that no change in systemic treatment after SBRT was significantly associated with an increased occurrence of the AE [45].

A more substantial body of evidence is available for lung cancer, with NTER reported in 60 patients: 7 from case reports [48–51, 53, 55, 58], and 53 out of 251 (21%) from retrospective [54, 57] and prospective studies [52, 56], with an additional 3 cases from Ito et al. [45]. Separating retrospective from prospective studies, NTER occurred in 34 out of 217 (16%) patients and 19 out of 34 (56%) patients, respectively. Recent advances in lung cancer treatment involve adoptive cell therapies such as CAR-T, TCR, and TIL [89]. Notably, recent trials for lung cancer patients without targetable oncogenic driver alterations have demonstrated significant and sustained responses to PD-1/PD-L1 checkpoint blockade immunotherapies [90]. In thoracic tumors, NTER has been reported not only in combination with immune or targeted therapies but also with other agents that activate the immune response. For example, combining therapeutic cancer vaccines with immune checkpoint inhibitors has shown improved therapeutic effects [91, 92]. One notable study, a mono-institutional phase II trial [52], investigated innovative SBRT targeting partial tumor hypoxic clonogenic cells (SBRT-PATHY) in unresectable bulky NSCLC. This study demonstrated significant non-targeted effects by sparing the peri-tumoral immune microenvironment and regional lymphocytes, with distant tumor response achieved in 9 out of 20 patients.

The ongoing ABSCOPAL-1 clinical trial [56] is exploring the combination of nivolumab and SRT after failure of first-line therapy. This trial aims to determine if SRT can enhance the response to nivolumab and reduce the frequency of its administration, while nivolumab may amplify the AE initiated by SRT.

A single report is available for thymic malignancies, stemming from a retrospective multicentric study [47].

Table 3 provides an overview of each study reviewed for thoracic tumors.

AEs in gastrointestinal (GI) malignancies have been primarily documented in isolated case reports [59–64]. Esophageal cancer, the sixth leading cause of cancer-related mortality globally, often relies on radiotherapy as a cornerstone of treatment. However, therapeutic options for recurrent advanced disease remain limited. Ongoing clinical trials are investigating the potential of combining IT with RT in these patients [93, 94]. Among immunotherapies, pembrolizumab has demonstrated superior efficacy compared to CHT as a second-line treatment for advanced esophageal cancer.

A few single cases have also been described for metastatic oligoprogressive cholangiocarcinomas [64], treated with a combination of SBRT and IT. Metastatic or recurrent intrahepatic cholangiocarcinoma (ICC) typically carries a poor prognosis [95], due to its limited sensitivity to CHT, radiotherapy, and IT when used in isolation. In preclinical studies, RT appears to increase PD-L1 expression on tumor cells, enhancing T-cell recognition [96], which makes PD-1 blockade a potential therapeutic opportunity.

Straddling the line between pulmonary and GI neoplasms, two cases of dual possible primaries have been reported [59, 74]. Chino et al. [59] described an SBRT-induced AE in a patient with HCC following treatment for localized NSCLC. Additionally, Kim and Kim [63] reported a case where liver metastasis resolved in a patient with two distinct primary malignancies. Furthermore, AE in HCC was notably featured in a phase II trial [74], where ipilimumab was combined with SBRT for metastatic disease. In exploratory analyses of non-target lesions, it was found that lesions receiving low-dose radiation were more likely to exhibit a response than those receiving no radiation.

Table 4 provides an overview of each study reviewed for GI tumors.

Renal cell carcinoma (RCC) is another tumor that has historically shown resistance to radiation. Surgery remains the standard treatment; however, local recurrences occur in over 30% of patients, and distant metastases develop in another 30%. RCC cells have a low alpha-to-beta ratio, which means they do not respond well to conventionally fractionated RT, owing to their inherent ability to repair sublethal DNA damage [97]. As a result, SBRT has become an attractive treatment modality, particularly for controlling extracranial RCC metastases, which commonly affect the bones and lungs.

New treatment options, such as tyrosine kinase inhibitors (TKIs) and checkpoint inhibitors, have been established as effective therapies for metastatic RCC, but only a minority of patients achieve a CR. To enhance treatment efficacy, one promising strategy combines TKIs and checkpoint inhibitors with RT, thereby increasing RCC sensitivity as demonstrated in preclinical studies [98]. However, clinical experience with this approach is limited to just 7 patients: 5 from single cases [65–67, 70, 71] and 2 from prospective studies (8.7%) [68, 69]. The first reported non-targeted effect following stereotactic radiation in RCC was documented in 2012 [65]. In 2019, Dengina et al. [68] published a prospective cohort study demonstrating that SBRT to extracranial metastases of RCC was well tolerated when combined with targeted or IT, resulting in partial or CRs in the treated lesions in most patients. A secondary endpoint of the study was the evaluation of non-target responses, where one patient out of 17 experienced an AE. Two years later, a prospective multicenter study [69] showed the highest frequency of NTER, with one patient experiencing the effect out of six. This study used SBRT in an innovative neoadjuvant setting, and the patient remained disease-free for three years without additional therapy.

The experience for bladder cancer is even more limited, with only a single case report available [72]. Clinical trials have demonstrated activity of pembrolizumab in prostate cancer [99, 100]. Higa et al. [73] assessed the clinical profile of 54 patients treated with pembrolizumab to identify factors associated with tumor response and toxicity. Ten men received SBRT to an isolated metastasis shortly before or during pembrolizumab treatment with the goal of inducing an AE. Although they confirmed that pembrolizumab, with or without supplemental SBRT, has modest but real anticancer activity in men with prostate cancer, particularly when treatment is initiated at an earlier disease stage or in patients with lower cancer volume, a clear NTER was not described.

Table 5 provides an overview of each study reviewed for genito-urinary tumors.

Primary malignant bone tumors are quite rare [101], which explains the limited reporting on these cases. Mizumatsu and Nomura [82] have recently reported the only experience in abscopal response after SBRT for a diffuse large B-cell lymphoma (DLBCL) of the skull.

Soft tissue sarcomas are aggressive tumors that often present with metastatic disease. Due to unsatisfactory tumor control with classic CHT, other systemic treatments have been tested, such us immune therapy with anti-PD-1. Preclinical studies have demonstrated that combining SBRT with anti-PD-1 therapy can enhance both the local and systemic immune response. This combination leads to massive cancer cell lysis, releasing tumor-associated antigens and stimulating the translocation of calreticulin to the tumor cell surface. Calreticulin and these antigens activate antigen-presenting cells, including macrophages and dendritic cells, which release pro-inflammatory cytokines and activate CD8+ cytotoxic T cells to target cancer cells [102, 103]. However, the clinical experience regarding the combination of SBRT and IT in sarcomas is limited [84]. A single case report did not provide sufficient data for definitive conclusions; however, the occurrence of an AE in a tumor as radioresistant as sarcoma is suggestive.

In addition to the studies already mentioned, NTER have been reported in at least 83 other patients across studies not focusing on a specific tumor type [74–81]. Menon et al. [75] performed a post-hoc analysis of three ongoing immune-radiation trials. They compared lesions that received low-dose radiation to those that received no radiation and found that low-dose radiation could enhance the systemic response rates of metastatic disease treated with high-dose radiation and IT. Building on these findings, Tubin et al. [76] conducted experiments using the SBRT-PATHY approach, which was tested in both the aforementioned prospective trial [46] on bulky or unresectable NSCLC and a retrospective study on various cancers (Figure 5).

In a recent retrospective analysis by Zagardo et al. [79] about immunorefractory oligoprogresive patients, NTER were hypothesized but didn’t occur during the observation period. More promising are the results from a multi-group prospective study by Chang et al. [80], which found that 38.5% of patients with various advanced solid tumors exhibited out-of-field disease control after combining SABR with IT, with the response rate reaching up to 50% in the nivolumab group. A similar response rate was reported by Zafra et al. [81].

Table 6 provides an overview of all reviewed studies not included in previous chapters.

This review concludes with a critical emphasis on the essential baseline information that future studies should report:

1.

NTER should be included as at least a secondary endpoint.