Stereotactic radiotherapy technique is widely used in the treatment of limited metastatic disease (20). Cranial SRS/FSRS are effective treatment options in patients with a limited number of BM showing good local control rates (21-22). However, metastatic patients often present with multiple or large BM, poor clinical conditions, uncontrolled primary and tumor spread related symptomatic. Sometimes, this unfavorable category of patients is selected to WBRT or BSC (23).
WBRT is used to treat multiple brain metastases addressing both visible and microscopic tumors and could help prevent the development of new metastases in other brain areas. The SIB component allows for the delivery of a higher radiation dose to specific tumor regions within the brain. This is often based on the size and location of the metastases.
In the literature, there are only retrospective series regarding WBRT-SIB in patients with intracranial metastatic disease (See Table 3). Overall, there are about > 400 treated patients in the past 5 years. Most of them were NSCLC patients; a few patients presented with breast cancer, melanoma, SCLC or a primary tumor in the GI tract (8, 13, 17, 22). Mainly, WBRT-SIB was performed among patients with 1-4 BMs, a few of them had between 4 and 10 BMs and a very few patients presented with > 10 BMs. In the current study, unfavorable patients with large/multiple BMs and high brain tumor burden (median PTV SIB volume 18 cc) were considered for WBRT-SIB. Fifteen patients had a KI ≤ 80%, median number of BMs was 8 for the entire series and 15 patients (43%) had ≥10 BMs. Brainstem metastases and limited leptomeningeal disease were no exclusion criteria to consider a WBRT-SIB. However, only 37% of the patients had a NSCLC diagnosis; patients with SCLC and melanoma were also considered for this treatment option.
Principally, WBRT-SIB dose was 30Gy in 10 fractions for WBRT with a simultaneously applied Boost up to 40-52 Gy in other series (9-10, 14-15, 19). However, fractionation and dose are inhomogeneous, even though the treatment was delivered in 10 up to 15 fractions. In our series, 35Gy (WBRT)/42Gy (SIB)/14 fractions was mostly used.
In the current literature, iPFS ranged between 3 and 20 months, often about 9-14 months, and OS ranged between 10 and 32 months, often about 20 months. In our series, median iPFS was not reached and the 1-year iPFS was 75%. The 1-year OS was about 25% (median < 9 months). Our results are in line with the current literature emphasizing a benefit of dose escalation also in multiple or large brain metastases by achieving good local and intracranial control. The possible advantages of local dose escalation include the following therapeutic goals: Firstly, significant tumor regression can be achieved in large metastases that would otherwise lead to irreversible symptoms. Furthermore, significantly better intracranial control can be achieved in patients undergoing systemic therapy with an unclear response probability due to insufficient intracranial availability of the chemotherapy or immune checkpoint inhibition (ICI) therapy used. On the other hand, a good patient selection and further findings regarding prognostic factors in an apparently unfavorable population could help to define subgroups due to the present low OS.
WBRT-SIB was reported to be well-tolerated with occasionally grade 3 toxicity (9-12, 14-19). A hippocampus-sparing technique has been developed over time because of significant neurocognitive decline following WBRT (24). Radiation planning with hippocampus-sparing is complicated and requires high expertise (13) in case of WBRT SIB in patients with up to 10 metastases. In the real life, patients present with >10 BMs, grown symptomatic and they need a quick treatment administration. Moreover, in our series patients had oft metastatic growth in the hippocampus region: a sparing of the hippocampi was passible only in 3 patients.
Some of the recent studies compare WBRT-SIB to other treatment options as WBRT-SEB and WBRT+SRS (14-16,19). Basically, contradictory results have been reported. Lin et al. demonstrated a significant benefit in terms of iPFS after WBRT-SIB vs. WBRT+SRS (9.1 vs. 5.9 months, P = 0.001). Another study by Du et al. showed a significant OS benefit in the WBRT-SIB group (14 months) vs. WBRT alone (7 months, p < 0.001) and WBRT-SEB (11 months, p = 0.037) (16). Instead, the retrospective analysis by Quing et al. demonstrated a significant improvement in OS in the WBRT-SEB group 15 mo vs. 10mo of the WBRT-SIB group and also better-preserved cognitive functions in favor of the WBRT-SEB group (18). At the present, there is a lack of prospective data or at least large series of patients to draw validated conclusions, and retrospective data might suggest that a form of boost to the macroscopic intracranial disease might be superior to WBRT alone in selected cases.
Recently, efforts have been done to combine last generation systemic therapies to WBRT-SIB in patients with multiple BMs also compared to standard WBRT in NSCLC patents (12, 14). The number of treated patients is very small, and a real difference of the addition of the drug to WBRT versus a monotherapy was not detected. It could only be assumed that a combination of systemic therapy to WBRT (+/-SIB) in terms of tolerance is feasible.
Most of the evidence for WBRT-SIB comes from retrospective series, indicating a need for further prospective studies to better establish the efficacy and safety of this treatment approach.
The limited number of patients in these studies (around 400 in the past 5 years) underline the need for larger cohorts and longer-term follow-up to draw more robust conclusions.