Radiosurgery or hypofractionated stereotactic radiotherapy for brain metastases from radioresistant primaries (melanoma and renal cancer)

About 10 and 50% of patients with renal cancer [1] or melanoma [2], develop brain metastases during the course of their disease respectively. Multimodality treatment including neurosurgery, radiotherapy, systemic treatments, and best supportive care with respect to disease burden, patient preference and performance status is usual. Stereotactic radiotherapy has become a standard of care for patients with a limited number of brain metastases [3, 4]. This is so regardless a histology-based approach despite different spread patterns and different response to the various treatment modalities. On the basis of such results, in our institution, we treat patients having up to 10 brain metastases from melanoma or renal cancer with stereotactic radiotherapy. Given the radioresistant nature of melanoma and renal cancer, optimization of the fractionation of stereotactic radiotherapy is needed. Following the linear quadratic model [5], and considering an α/β ratio about 2.5 [6, 7], then biological effective dose is much higher with SRS (>18Gy) than with HFSRT. Thus, it was expected that brain metastases of radioresistant primary tumors treated with HSFRT would show poorer local control than these treated with SRS. Indeed, a retrospective study with a small sample concluded that fractionated stereotactic radiotherapy was less effective in radioresistant tumors and recommended that radioresistant tumors should be treated in a single fraction if possible [8, 9]. The linear quadratic model has been suggested to be incorrect for large dose fractions, because it does not take into account additional biological effects resulting from high dose on endothelial cells and tumor immunity. Thus, local control could be not strictly correlated to calculated biological effective dose.

In this retrospective study we aimed to examine if hypofractionated stereotactic radiotherapy impacts local control of brain metastases from radioresistant tumors such as melanoma and renal cancer.

This single center retrospective study has been led in order to explore the impact of stereotactic radiotherapy fractionation on local control of small radioresistant brain metastases. The analysis was conducted on 60 patients and a total of 193 metastases smaller than 3 cm with a median follow-up of 7.4 months between 2013 and 2016. To the best of our knowledge, it is the largest published collection, dealing with the impact of fractionation on local control of only radioresistant brain metastases. Local control at 12 months was 74%, closer to control rates reported in recent retrospective studies, which range from 81 to 91,5% [7, 16‐23].

Whereas until now, there was mounting evidence that HFSRT was an effective approach in terms of local control for larger brain metastases or radiosensitive histologies [24], similar results, to our knowledge, have not been mentioned for smaller and radioresistant brain metastases.

On the basis of the linear quadratic (LQ) model [25], considering an α/β ratio of about 2.5, SRS patients received a median BED_2.5 of 180Gy and HFSRT patients a BED_2.5 from 122Gy for the 6 × 6 Gy schedule to 150Gy for the 3 × 10 Gy schedule. Unexpectedly, better local control was not observed in the SRS subgroup as HFSRT was equivalent to SRS in terms of local control. These results are quite different and contradictory with Oermann’s [8]. In fact, in a smaller study with a subgroup of 99 radioresistant brain metastases, he described a trend toward improved local control for single-fraction radiosurgery [8]. However, even if dose per fraction was not reported in that study, the median delivered dose was 20Gy. It was much less than in our study where patients in the HFSRT group received a median dose of 30Gy. Higher dose per fraction and total dose in HFSRT group improve the efficacy of fractionated radiotherapy.

In our series, the LQ model was clearly not predictive of local control, and we believe that LQ model is inadequate in these situations. Indeed, LQ model is based on the assumption that radiation-induced cell death in tumor is due to DNA strand breaks. Then LQ model underestimates the role of indirect cell death by devascularization and radiation induced immune enhancement [26, 27]. Radiation-induced apoptosis of endothelial cells, leading to indirect tumor cell death, is predominant for dose per fraction higher to 10 Gy [28], and consequently, here, it could not explain our results. Concerning radiation immune effects, recent pre-clinical studies support a superior anti tumoral immune enhancement effect for high dose fractionated radiotherapy (>8Gy) than for single fraction irradiation [29, 30]. Here, our study dealt with melanoma and renal cancers, which are classified as ‘immunogenic’ tumor, based on several characteristics: incidence of spontaneous tumor regression, high level of tumor T-cell infiltration and responsiveness to immunotherapies such as interleukin 2 (IL-2) interferon alpha (IFN-α) or Anti PD1 [31]. On these arguments, the “unexpected” good local control rate for HFSRT-treated metastases could be due to a better radiation-induced immune enhancement. Nevertheless, this hypothesis is based on pre-clinical studies or case reports studies, and should be studied and discussed in prospective trials [32, 33].

One of the other interesting points raised in our analysis concerned the delay in initiating radiotherapy after fusion MRI. When radiotherapy was delayed from more than 14 days after fusion MRI, local control at 6 and 12 months decreased from 96 and 86% to 77 and 70% respectively (p = 0.009). For these patients, delays in workflow could make pretreatment imaging inadequate for SRS or HFSRT planning, and thus, as the tumor continues to grow the reduced margins used in these treatments, become insufficient to cover the whole target. The same cut off of 14 days was reported by Seymour et al. [34]. In this study, the 6- and 12-month LPFS rate were 95 and 75% for metastasis with interval of < 14 days from MRI to treatment compared to 56 and 34% for metastases with MRI ≥ 14 days before treatment. In our study, fusion MRI was obtained on the same day as simulation for 31% (n = 60) of mestastases. For 27% (n = 52) of metastases, MRI was obtained after simulation, and for 42% of metastases (n = 81) a new MRI was not acquired at or after simulation. In this case, the diagnostic MRI, with sufficient transverse images was used. This last group participate to extend delay from MRI to treatment and could explain extreme values and why the delay is quite long in our serie. The extreme values corresponded to the first patients treated with the Cyberknife in our institution on January 2013. To conclude, time from MRI to SRS or HFSRT should be the shortest as possible, and delaying the beginning of the treatment should be absolutely avoided, as confirmed in propensity score matching analysis.

OS and CPFS remain disappointing, and stereotactic radiotherapy could not be considered as a single modality treatment. Poor CPFS was expected. In fact, stereotactic radiotherapy offers to patients good local control rate, while avoiding neurocognitive late effects, but with more cerebral distant relapse in comparison with SRS/HFSRT plus WBRT [4].Nevertheless, when cerebral distant relapse occurs, HFSRT/SRS rescue treatment still remains possible and WBRT can be delayed. For example, in our study, 37% of the patients had received a second or a third session of stereotactic irradiation with excellent outcomes. And for only 27% of the patients, a rescue WBRT was needed.

The main limitation of our study is its retrospective nature. It suffers from the shortcomings of all retrospective studies. The two compared groups are not strictly similar; the major difference being the size of the target volumes. For example, in SRS group, GTV volumes were quite smaller than HFSRT group. Assignment to single fraction irradiation or HFSRT was not random and based on GTV volume and localization. It could lead to selection biases in terms of treatment choice. However, to limit this selection bias, we performed a propensity score matching analysis, which makes the comparison more robust (the two experimental groups were comparable), and lead to similar conclusions. Furthermore, in our study, the radionecrosis rate was quite low, about 9%, whatever the fractionation. For HFSRT treated metastases, this rate was similar to others studies [24, 35, 36]. On the opposite, contrary to our results, for SRS treated metastases, several authors reported radionecrosis rates much higher than our study with rate superior to 20% [24, 37]. This difference could be explained by different ways. First, given the poor overall survival of our population, follow-up (7,4 months) was too short to see the emergence of fewer radionecrosis. In Minniti’s [24] and Kohutek’s [37] studies, follow-up were much longer, 29 months and 17.2 months respectively, but with a high proportion of non-small cell lung cancer brain metastases. Most of the time, radionecrosis occurs 10 to 12 months after stereotactic radiotherapy [37]. Secondly, in our institution, multi-parametric MRI or F-DOPA PET-scan were not systematically performed during the post stereotactic radiotherapy brain metastases follow-up period. Thus, our diagnosis criteria were probably less sensitive than in other studies to detect radionecrosis.

As a conclusion, this is the largest retrospective study evaluating the impact of stereotactic radiotherapy fractionation on radioresistant brain metastases. Fractionation does not seem to decrease LPFS. Even for radioresistant smaller brain metastases (< 3 cm), HFSRT, with 3 or 6 fractions, leads to an excellent local control rate of 72% at 1 year with only 7.1% rate of radionecrosis. HFSRT is a safe and efficient alternative treatment to SRS. In case of proximity of highly functional zones, such as brainstem or cavernous sinus, the radiotherapist can safely propose a 3 or 6 fractions schedule, subject to dosimetric constraints respect, without compromising local control, even if the metastasis is small.

These data have to be confirmed by a prospective randomized trial. Whatever the irradiation fractionation, the radiotherapist should make the necessary efforts to begin the treatment less than 14 days after MRI fusion, in order to ensure optimal local rate.