Background
Novel linear accelerator technology allows compensating non uniform photon fluence by use of intensity modulation instead of directing the beam through a flattening filter. A major advantage of using flattening filter free (FFF) beams is that the dose rate can be multiplied in comparison to flattened beams thereby shortening beam-on time [
1,
2]. This is especially attractive when a high dose per fraction is used, e.g. in the case of stereotactic body radiotherapy (SBRT). Although FFF beams at maximum dose rate have been rapidly introduced into clinical use, little clinical data about their safety and efficacy are available.
Shortening of treatment time improves patient comfort especially in elderly and frail patients and was shown to improve patient stability [
2-
4]. On the other hand, it may introduce novel hazards, e.g. in case of patient or organ movement there is less time to intervene. There are also dosimetric uncertainties due to the interplay effect; e.g. Ong et al. [
5] investigated the dosimetric impact of intrafractional motion during spine radiosurgery and found an increased sensitivity of the target coverage and dose to the spinal cord if FFF beams are used compared to flattened beams.
Because of putative unknown radiobiological hazards of using high instantaneous dose rate, several research groups recently performed preclinical investigations. Using exclusively
in vitro assays, four studies could not detect any effect of high dose rate on clonogenic cell survival [
6-
9], whereas Lohse et al. [
10] found that FFF beams given with high dose per pulse impaired clonogenic survival and this effect became significant with high dose per fraction. Only one preclinical study so far investigated the effect of extremely high dose rate
in vivo. Using a murine lung fibrogenesis model as well as human xenografts and murine syngenic and orthotopic lung tumors a differential response between normal and tumor tissue in mice was shown when ultrahigh-dose-rate flash irradiation was compared to conventional dose rate irradiation [
11]. Also classical radiobiological considerations seem to support a dose rate effect of very high dose rates. Based on the linear quadratic model, in a recent comprehensive review it was suggested that the influence of high dose rate on tumor response and toxicity is determined by beam-on time with late reacting tissue being more sensitive to dose rate effect than tumors and early reacting tissues [
12].
Our clinic was the first to use FFF linear accelerator technology at maximum dose rate for SBRT in patients. With the lack of a clear biological rationale not to use FFF beams we introduced this technology assuming that the benefit in terms of increased treatment efficiency would outweigh the minimal risk of additional toxicity. Here we report the results of our patients with focus on patient safety, which is the biggest patient cohort reported so far.
Discussion
In the present study we analyzed the clinical results of the patients treated with SBRT and FFF beams at maximum dose rate at our institution. We included all patients treated so far, although it is a hetergenous cohort, because we wanted to analyze overall patient safety and detect any unexpected toxicity rather than investigating specific tumor sites. We show in 84 patients with 100 lesions in the lung, liver, adrenal glands, lymph nodes and other sites that the use of FFF beams for these indications is associated with low rates of acute and early late toxicity and results in excellent early local tumor control. The results shown appear similar to results of studies using SBRT with flattened beams and lower dose rates.
Most of the data published about FFF beams explored their physical properties [
1,
2,
13,
21-
25]. Altogether these studies show that the use of FFF beams significantly reduces treatment time for high single fractions and dose distributions are comparable to flattened beams. Apart from the technical benefits there have been some concerns about patient safety when FFF beams with high instantaneous dose rate are used due to physical uncertainties of beam application and biological considerations.
A physical concern is that very short beam-on times introduce dosimetric uncertainties in case of tumor shifts. In patients with spinal metastases Ong et al. [
5] investigated shifts of 1–5 mm during 5–30 seconds in the case of single fraction SBRT with flattened or FFF beams. Dosimetric deviations in FFF plans were approximately 2-fold greater than with flattened beams, which resulted in significant overdosage of the spinal cord and underdosage of the GTV with increasing shift size and dependent on shift duration. In their study GTV to PTV margins of 2–3 mm were used. In our clinic until recently we did not use SBRT for spinal metastases and therefore the lesions analyzed had usually less proximity to critical organs. In addition we fractionated SBRT und applied much larger margins (3–10 mm). Therefore potential dosimetric uncertainties are much less important for the treatments reported by us.
Recently several preclinical studies were published investigating the biology of high instantaneous dose rate in clonogenic cell survival assays [
6-
10]. Sorensen et al. used Chinese hamster and FADU cells irradiated with 6 MV flattened beams with single doses up to 10 Gy, dose rates between 5 and 30 Gy/min and instantaneous dose rates per pulse between 56 and 338 Gy/s [
8]. They did not find any effect of high instantaneous dose rates on cell survival. In contrast, Lohse et al. [
10] irradiated different glioblastoma cell lines using 10 FFF beams with overall dose rates of 0.2 Gy/min or 24 Gy/min and instantaneous dose rates per pulse up to 350 Gy/s and found that high dose per pulse but not delivery time reduced clonogenic survival. The anti-tumor cell effect of high dose rate increased with fraction size and became significant at 10 Gy. Three additional preclinical studies were published investigating FFF beams in different cell-lines, all showing no difference in clonogenic cell survival if FFF beams with dose rates up to 24 Gy/min are used [
6,
7,
9]. A preclinical study using clinically more relevant
in vivo models was recently published by Favaudon et al. [
11]. The authors used a lung fibrogenesis model and human tumor xenografts as well as syngenic and orthotopic murine lung tumors and treated them with high single fractions of ultrahigh-dose-rate flash irradiation (dose rate ≥ 40 Gy/s) versus conventional dose rate irradiation (≤0.03 Gy/s). Interestingly both techniques exerted similar anti-tumor effects but the ultrahigh-dose-rate flash irradiation induced much less TGF-β dependent lung fibrosis indicating a differential response between normal and tumor tissue. A somehow contrary differential effect was recently suggested and modeled by Ling and coauthors considering various factors such as different mechanisms of DNA repair and implications of the α/β model [
12]. Their conclusion was that the dose rate effect is not determined by the instantaneous dose rate but instead by beam-on time, which mostly affects late reacting tissues. By computing with the LQ Model they calculated for example that, if a single fraction of 10 Gy is given in 2 minutes instead of 10 minutes, this acceleration increases BED to the tumor (α/β = 10) by ~1.5% and BED to late responding tissue (α/β = 3) by ~3.9%.
We previously demonstrated that the gain in beam-on time by using 6 or 10 FFF beams in comparison to a 6 MV flattened beam increases with dose per fraction and amounts to several minutes when fractions beyond 10 Gy are used [
2]. Therefore based on the paper by Ling et al. there might be clinical situations, e.g. in case of spinal SBRT when high doses are given in close proximity to critical serial organs, when the use of FFF beams with maximum dose rate might lead to a small increase of complications.
Only few clinical studies so far investigated the clinical outcome of SBRT with FFF beams in patients [
26-
31] (Table
4). Almost all studies except the studies by Prendergast and Wang were conducted from the research group of the Humanitas Cancer Center in Milano [
26-
28,
30,
31]. Generally, patient numbers in these studies were small and the follow-up was short. In the biggest retrospective patient series, 67 patients with 70 lesions in different organs were treated with SBRT using FFF beams [
30]. The treatment schedules ranged from 32–48 Gy in 4 fractions for lung and 75 Gy in 3 fractions for liver tumors. With a minimum follow-up of 3 months two acute grade 3 lung toxicities (3%) were observed and 89% of patients showed a tumor response at 60–90 days after SBRT. In the only prospective study published with FFF beams so far, 40 prostate cancer patients were treated with 35 Gy in 5 fractions [
26]. After a median follow-up of 11 months no grade 3 toxicity was observed.
Table 4
Clinical studies investigating toxicity and outcome of SBRT with FFF beams
Patients (Lesions)
| 84 (100) | 20 (22) | 64 | 40 | 46 | 25 (28) | 67 (70) |
Tumor
| Various (mostly lung) | HCC | Lung | Prostate | NSCLC Stage I | Abdominal/pelvic LN | Various (mostly lung) |
RT schedule
| 21 – 66 Gy (3–15 fx) | 40 - 75 Gy (3–10 fx) | 30 – 60 Gy (3–5 fx) | 35 Gy (5 fx) | 48 Gy (4 fx) | 45 Gy (6 fx) | 32 – 75 Gy (3–6 fx) |
Median follow-up (range)
| 11 months (3–46) | 7 months (3–13) | 12 months (3–25) | 11 months (5–16) | 16 months (2–24) | 6 months (2–19) | NA7
|
Acute toxicity
1
≥ G3
| 0% | 5%3,6
| 2%4
| 0% | 4%4,6
| 0% | 3%4
|
Late toxicity
1
≥ G3
| 1%2
| 12%4,5
| 0% | 0% | - |
Local control
| 1-y-LC: 94% | Actuarial-LC: 95% | NA8
| NA8
| 1-y-LC: 100% | Actuarial-LC: 100% | Actuarial-LC: 89% |
In the studies of the Milano group the dose was prescribed homogeneously to the 95% isodose [
26-
28,
30]. In contrast, we use a SBRT protocol, where the dose is prescribed inhomogeneously to the PTV with dose maxima in the tumor of up to 152%. Therefore, in case of similar dose prescription, the patients reported by us received a substantially higher dose to the GTV and immediately surrounding PTV without evidence of increased toxicity. The only study that reported substantial high-grade toxicity when using SBRT with FFF beams was published by Prendergast et al. [
29]. This study included 64 patients with lung malignancies receiving 30–60 Gy in 3–5 fractions. Median follow up was 11.5 months and 6 cases of severe ≥ grade 3 late toxicity (12%) occurred; of these, five were pulmonary and one nerve-related. One patient died because of sepsis after pneumonia in the irradiated lobe. Tumor control and survival data were not presented.
We report a 1-year local control rate of 94%. All tumors treated with a PTV surrounding BED > 100 Gy were locally stable after one year and small lung tumors ≤ 14 cm
3 (~3 cm diameter) had a significant lower recurrence rate. Dependency of tumor control on BED and tumor size is well known from studies predominantly performed with flattened beams [
19,
32,
33]. In addition, the toxicity reported by us is similar or even lower in comparison to the toxicity reported in the literature for SBRT with flattened beams [
17,
34-
36]. In order to detect small changes in toxicity, when FFF beams are used, large randomized studies would be needed, which are unlikely to be performed, because FFF beams are rapidly adopted into the clinic and are FDA-approved. In addition to LCR and toxicity we also analyzed PFS and OS. Of clinical importance, the PFS was much lower than the LCR suggesting that patients tend to recur distant from the irradiated lesion. In addition, the low numbers of 1-year PFS and OS in primary and secondary cancers indicate a selection bias of inoperable, comorbid or extensively pretreated patients.
A limitation of our study is the retrospective design, which doesn’t allow evaluating all side effects of radiotherapy in the same manner. On the basis of medical records we often could not distinguish between toxicity grade 1 and 2, therefore we focused on side effects of grade 3 and higher: events that made hospitalization or prolongation of hospitalization necessary. Because of only one case of ≥ grade 3 toxicity we could not perform statistical analysis of toxicity related risk factors (e.g. radiation dose, tumor size, centrally located vs. peripheral lung tumors, etc.). Although our clinic was the first center to implement FFF beams for clinical use, the median follow-up of 11 months is relatively short with, on the other hand, the follow-up period ranging up to 41 months.
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Competing interests
The authors declare that they have no conflicts of interest.
Authors’ contributions
SS carried out the data analysis, performed statistical analysis and drafted the manuscript. SL participated in data analysis and statistical analysis. CL helped to analyze toxicity. SG participated in data analysis. OR conceived of the study, participated in study design and data analysis and helped to draft the manuscript. All authors read and approved the final manuscript.