Introduction
Stereotactic radiosurgery (SRS) is considered standard therapy for oligo (1–3) brain metastases (OBM) [
1‐
3]. The treatment of multiple (>3) brain metastases (MBM) with SRS vs. whole-brain radiotherapy (WBRT) is subject to debate [
4‐
6]. Some studies suggested that not the number of metastases but clinical factors like performance status, histology and extra-cranial manifestations are leading survival factors [
6,
7]. Furthermore, for melanoma (MLA), non-small-cell-lung-cancer (NSCLC), breast-cancer (BC) and renal-cell carcinoma (RCC) and concomitant with targeted therapy or immunotherapy (TT/IT) there is now sufficient evidence of efficacy and safety for MBM-SRS [
8‐
11].
Nonetheless, technical challenges for MBM-SRS remain which include dose delivery over time to all tumor cells and simultaneous minimization of healthy brain dose. To achieve this, precise treatment delivery with small safety margins and numerous beam directions and/or isocenters to create steep non-intersecting dose gradients are necessary [
12]. However, the treatment complexity will automatically increase treatment time, which in turn will decrease the dose delivered to certain tumor cells within certain time spans. This phenomenon is called tumor-dose-rate (TDR) effects, which are loco-regional effects derived from dose-accumulation differences during treatment. Ultimately, the dose to most tumor cells (e.g., 98% [
13,
14]) in the gross tumor volume (GTV) or planning target volume (PTV) will reach the planned minimum dose (e.g., 16–20 Gy). However, for the dose delivered in, e.g., half the treatment time the situation may be different when some cells may have already received the planned dose while other cells may have not even reached the dose by far.
Biologically, the TDR phenomenon translates into the possibility of tumor cells receiving dose over longer periods of time to repair radiation-induced DNA damage during prolonged treatment. This has been reported for healthy cell lines [
15,
16]; however, for tumor cells the reports are somewhat inconclusive. One in-vitro analysis found no differences in tumor cell responses for long-pulsed vs. short-burst dose delivery [
17]. Another study even found that intermittent irradiation significantly reduced the survival of glioblastoma cells compared with continuous irradiation [
18]. On the other hand, TDR effects have been reported for Gamma Knife SRS (Elekta, Stockholm, Sweden), where changes in treatment plan complexity can influence treatment time and hence biological equivalent dose (BED) when including treatment time components [
19,
20].
In contrast, the main problem for CyberKnife SRS (Accuray, Sunnyvale, USA) arises from step-and-shoot delivery and regional-dose-rate effects have been reported for potential treatments of atrial fibrillation where healthy cells are targeted and dose-rate differences are expected to manifest clinically [
21]. Regardless, there is a clear lack in clinical data for in-vivo tumor configurations and the authors attempted to overcome this shortcoming by investigating the TDR phenomenon for CyberKnife MBM-SRS.
Discussion
For the first time, the authors demonstrated high local TDR variations for CyberKnife stereotactic radiosurgery. They found that maximum dose delivered over certain time frames during treatment is notably lower for multiple (>3) brain metastases as compared to oligo (1–3) brain metastases. This may translate into the possibility for some tumor cells to repair DNA damage during prolonged treatment and to re-populate to form local tumor recurrences. While DNA repair in prolonged dose delivery is well described for normal cell types [
15,
16],
in-vitro studies for tumor cell lines showed none or even opposite effects [
17,
18]. On the other hand, BED simulations which included treatment time components have shown negative impacts of more complex treatment plans and hence prolonged treatment on tumor control [
19,
20].
However, all studies lacked clinical outcome data correlation and the authors found that the
in-vivo response of brain metastases after SRS is notably different if the TDR during treatment is lower. Explicitly for locally responding metastases (complete/partial remission) they found higher mean TDR
60min,98% of 0.28 ± 0.17 Gy/min vs. 0.23 ± 0.12 Gy/min for non-responding metastases (local stable/progressive disease). This difference was similar in short- and long-term response. However, while their analysis may point to clinical influences of TDRs during treatment, they were not able to directly correlate low TDR with sole local progression due to low recurrence rates in their cohort. To some extent, this might be explained by shorter follow-up in the MBM group. The results may also be influenced by concurrent medication where the combination with TT/IT showed higher response rates as compared with concurrent chemotherapy or no concurrent medication. The synergistic effects of combined SRS and TT/IT are well described [
8‐
11,
28,
29], although local response is often not presented in greater detail. Additionally, local control is often correlated to dose and lesion volume, but the authors did not see any dose or lesion and/or volume based response differences in their analysis, which might be explained by GTV mean dose optimization [
24,
30,
31].
Technically, the TDR variations were also not correlated with lesion volume(s), depth of the lesion or any volumetric ratio or parameter. This may point to the possibility that the TDR can be kept constant with various collimators regardless of lesion size and location, limiting this statement to the lesion volumes presented in this work (0.01–4.64 cc). On the other hand, TDR variations were mainly driven by treatment time and each sub-factor like number of treated lesions, beams and beam directions as well as MU. This comes as no surprise as the CyberKnife treatment time can be split into equal thirds between imaging, robot motion and beam delivery time [
21], which directly correlates to number of beams, directions and MU, respectively. Especially the number of beam directions (robot motion time), even with optimized robot path traversal, is highly correlated to TDR with strong differences between <95 and 95–110 and >110 directions. However, a large number of directions and beams are needed in order to avoid hotspots between lesions and to ensure low exposure of healthy brain tissue [
23,
32‐
34], and a further increase in the CyberKnife working space [
35] will only worsen this specific problem. One possible solution may be reduced imaging frequency, although the authors already adapted the frequency to the patient position stability during treatment and a further decrease may significantly affect treatment accuracy [
36]. Another solution may come from increased linear accelerator dose-rates, but a change from our 800 MU/min linear accelerator to 1000 MU/min would have only resulted in a 4-min averaged treatment time reduction and a further increase in MU/min is currently not feasible for the small accelerator head.
Surely, one may switch altogether to different platforms with much higher dose-rates, but the in-treatment accuracy and possible dose gradients for intracranial SRS appear to still be inferior with c‑arm based linear accelerators as compared to dedicated SRS systems [
12,
23,
33,
34]. On the other hand, c‑arm based systems are capable of delivering dose during gantry rotation, which decreases treatment time tremendously. The newer CyberKnife version may also enable this option [
37], although it seems questionable whether this technique is feasible for multiple lesions treated simultaneously and further developments are surely necessary. Additionally, the use of multi-leaf-collimators for the CyberKnife (InCise, Accuray) [
38] may not result in adequate dose distributions for multiple small metastases as compared to cylindrical cones despite significantly reduced treatment times [
39]. Furthermore, not even the use of the dynamic Iris collimator (Accuray) [
40] may be able to resolve TDR variations as the necessary MU will be higher due lower output factors for the smallest field sizes [
41], and the beam repositioning towards multiple lesions in every direction may obliterate the benefits of reduced robot motion time with a single collimator, pending further investigation. Additionally, most metastases in this evaluation were targeted by the 5‑mm fixed collimator and for this field size the IRIS collimator is not advisable due to field size reproducibility concerns.
A real reduction of TDR variations may be achieved by smart collimator selection and plan splitting based on geometric regions of the metastases. The present results indicate that the use of single collimators for >4 lesions will notably decrease TDR. Since multiple collimators are beneficial for plan quality [
25], the collimator selection and delivery sequence could be optimized. However, this has already been performed in the present cohort to the extent possible and since the smallest field size (5 mm) is used for most lesions this option may be limited. On the other hand, plan splitting with only few brain metastases per plan or even per day may be feasible [
42], and the authors now use this possibility whenever the integral brain dose does not unreasonably increase. Other methods for increasing TDR may come from increased prescription dose, which is of course bound to healthy brain dose limits, and from fractionation based on isotoxic planning [
43], although this would only reduce the actual MU per session and hence affect only one third of the treatment time. A truly viable solution to the problem of low TDR during treatment may therefore only come from sequential beam delivery per actual treated target [
21]. However, this will of course increase the overall treatment time due to the higher robot travel required, which could then be countered by dose delivery during robot motion as already discussed [
37].
Limitations to the present analysis include the sample size (23 patients with 162 brain metastases), especially in the sub-groups, the mono-centric and mono-planner perspective, even though planning was based on international best practice guidelines, and the retrospective nature of the clinical response evaluation, even though the authorsʼ database was designed as a prospective register. Further limitations are bound to the nature of the patients’ diseases and the resulting limited life expectancy after developing multiple brain metastases. Hence, the statistical analysis for local control and response may be influenced by high censoring due to patientsʼ early demise. In the future and with higher sample sizes, the use of cumulative incidence functions under considerations of competing risks may be considered for analysis instead of the generally widely used Cox regression. Finally, further prospective analysis within multi-center cohorts which are based on the suggested optimization strategies for low TDR are necessary.