CNS malignancies account for an estimated 1.3% of new cancer cases annually and Glioblastoma Multiforme (GBM) is the most common (1). GBM accounts for 15.4% of all primary brain tumors and 45.6% of primary malignant brain tumors (2). Anaplastic Astrocytomas, another high grade glioma (HGG) accounts for 6.1% of all gliomas (3).
Standard of care for HGG entails maximal safe surgical resection followed by adjuvant radiotherapy (RT) and chemotherapy. Unfortunately, many patients recur within 5 to 8 months of definitive treatment (4). Historically, median survival after progression is 6 months (5). While the use of radiotherapy in the primary setting for HGG has been well established, the treatment paradigm in the recurrent setting is less elucidated and varies by institution (4-13). Salvage therapies used alone or in combination include surgery, re-irradiation, systemic treatment, tumor treatment fields (TTF) or palliation. Studies have shown a survival benefit with salvage treatment versus palliation (13). Currently, there remains a paucity of data and a lack of general consensus regarding the optimal management strategy for recurrent HGG.
Since the advent of stereotactic radiosurgery (SRS) and fractionated stereotactic radiotherapy (FSRT), more precise and focused targeting is now available and may be preferable in the re-irradiation/salvage setting (14). Various doses and fractionation schedules have been utilized, largely guided by location and volume of recurrence, with various levels of success. In general, SRS has been used for low volume disease while FSRT has been reserved for large volume recurrence (e.g., >4 cm), and allows safe delivery by taking advantage of the radiobiological benefits of fractionation (15,16). Given the poor prognosis of this patient group, efficacy must be balanced by the potential impact on patient quality of life. Herein, we review the various salvage RT series and their respective outcomes.
Radiobiology and physics of SRS and FSRT
There are key physics, radiobiologic, and dosimetric concepts to recall when evaluating SRS and FSRT regimens for recurrent HGG. From a physics perspective, the basic principles underlying conventionally delivered radiation therapy also guide the clinical use of SRS and FSRT. However, SRS and FSRT require a much higher level of accuracy given the modality delivers very high radiation doses over a single or few fractions. Millimeter-level precision is required in patient positioning with high reproducibility, which can be achieved either with a frame, or as is more common today, with a frameless, mask-based system (17). Target definition accuracy as well as precise image guidance is also critical with the small margins used in SRS and FSRT treatments. Radiobiologically, the literature suggests that high-dose, single fraction treatment primarily acts on tumor-supporting endothelial cells for its tumoricidal effects; in other words, the radiation response can be seen not only in the tumor cells themselves but also in the vasculature (18). The small margins required for SRS and FSRT limit collateral damage to normal tissues.
Kirkpatrick et al. noted that the immunostimulatory effects of SRS and FSRT are important to consider, especially with the growing role of immunotherapy in cancer treatment (19). They argue that although vascular damage may limit the ability of antigens to stimulate the immune system, a hypofractionated regimen such as FSRT, may leave antigen transport mostly intact and result in a stronger immune response than SRS. This is an emerging field of study which has the potential to shift the landscape of radiation techniques in the coming years.
In a recent systematic review of SRS in HGG the authors report a median overall survival (OS) of 20 months and progression free survival (PFS) of 5.42 months. In this study, the pooled rate of radiation necrosis (RN) was 5.9% but ranged from 0–44% (20). Another review deems SRS a safe and effective minimally invasive treatment for recurrent HGG. They report OS of 13–26 months after recurrence (21).
Several prospective trials and retrospective studies have explored dose and fractionation schedules for SRS in recurrent gliomas (Table 1). Doses ranged from 9 to 25 Gy. In some cases, up to 9 lesions were treated with SRS. Others limited SRS to small lesions which were defined differently depending on the study. Generally, doses were attenuated based on size and location of the lesion. Larger lesions and those in proximity to critical structures were prescribed lower doses.
Koga et al. published a study detailing the local control benefits of extended-field SRS. They evaluated the impact of adding a margin of 0.5- to 1.0-cm around the enhancing tumor. This study reported a statistically significant difference in local control between extended-field and conventional SRS. However, OS was not statistically significant between conventional and extended-field SRS groups and rates of RN were slightly higher in the population (n=9, 35 lesions) studied (26).
Historically, median survival from progression for GBM has been reported as 6 months whether the patients were treated with RT and TMZ upfront or not (5). Studies included in this review had a median OS from SRS ranging from 7 to 14.4 months with a median of 10.6. However, about half (10) studies included both WHO grade III and grade IV gliomas which may favorably skew the OS.
The majority of HGG will recur within 2 cm of the initial (pre-surgical) tumor bed which makes previous RT pertinent to the safety of re-irradiation (27,28). Normal tissue radiation tolerance is dependent on the volume treated, dose, and sensitivity of tissue being treated. Due to the highly conformal nature of both SRS and FSRT, treatment margins are eliminated and less healthy brain tissue is included in the field. This is especially relevant in the recurrent setting in which the majority of patients have already received RT to the area in question (15).
RTOG 9005 explored maximum tolerated dose of SRS in patients with a history of prior RT in primary brain tumors. Although the trial did not focus on gliomas with previous RT up to 60 Gy, it showed that maximum tolerated doses varied based on tumor diameter and that tumor diameter correlated with risk of grade ≥3 neurotoxicity. Twenty-four Gy, 18 Gy and 15 Gy were defined as the maximum tolerated doses for tumors ≤2, 2–3 and 3–4 cm respectively (29). Several phase I dose escalation trials have shown varying risk of radionecrosis when utilizing doses above those in RTOG 9005 (30-32).
RN is perhaps the most serious late side effect of CNS RT. It occurs in brain tissue that has received a normalized tissue dose (NTD) of >100 Gy. Changes in RT technique at re-treatment have not been correlated with an increased risk of this phenomenon. Low initial dose and long intervals between treatments may lead to less neurotoxicity (33-35). Clinically, RN can imitate tumor recurrence with worsening presenting symptoms, new neurological deficits as well as progressing enhancement on imaging. It may ultimately require surgical debulking. Other less invasive treatments may include bevacizumab, corticosteroids or hyperbaric oxygen (15,36).
Some studies showed no grade 3 or higher toxicities while others demonstrated that up to 26% of patients suffered clinically significant toxicities. A phase I dose escalation trial showed clinically significant toxicities of up to 60% however there were only 10 patients enlisted in the trial. Only one experienced neurotoxicity and other toxicities were associated with the concurrent systemic therapy (32). In one institutional report, 26% of 174 GBM patients underwent salvage craniotomy for RN. This report found that larger mean treatment volumes may have predicted for RN. Median volume of lesions treated with SRS in this retrospective study was 7 cc with a maximum of 39 cc (37). Another report found that 23% of patients experienced RN, however, this only represented 3 patients all three of which had different treatment volumes and different doses (38). Kong et al. reported a 24.4% RN rate but further analysis was not commented on. All of these studies used a median of 16 or 17 Gy (39).
Only one patient in a study by Sutera et al. experienced RN (grade 2), but not all patients were strictly treated with SRS. They included up to 8 fractions in their retrospective analysis (40). Another report found only one patient to have RN out of their 42-patient cohort. Additional disease-specific data was not offered regarding this patient, but the median dose in this study was 20 Gy (41).
Cabrera et al. included neurocognitive testing and quality of life parameters in their prospective trial of concurrent SRS and bevacizumab. This was assessed through the Mini-Mental State Examination (MMSE), Trail Making Test Parts A and B (TMT-A/B) and Functional Assessment of Cancer Therapy-Brain (FACT-Br) at baseline, 1 week and 2 months after SRS. Although they reported that neurocognition didn’t change during treatment, the physical well-being subscale of the FACT-Br showed significant worsening at the two-month time point compared to baseline or one week evaluations (42).
Varying combinations of systemic therapy and steroids were used in these studies. Doses of these agents also varied. Some patients were pretreated with steroids and others weren’t treated with steroids until clinical symptoms worsened. Not all concurrent or adjuvant treatments were detailed in published reports of the included studies.
Bokstein et al. reported a significant survival advantage in GBM patients treated with SRS vs. bevacizumab alone (12.6 vs. 7.3 months) (43). However, tumor burden and volume was not matched in this retrospective study and 40% of the patients in the SRS group received concurrent chemotherapy or biological therapy. Sutera et al. described an association between bevacizumab and inferior outcomes, however, only two patients received bevacizumab in their analysis (40). In contrast, Cuneo et al. described a survival benefit in patients receiving adjuvant bevacizumab after salvage SRS (11.2 vs. 3.9 months). They also reported a PFS benefit in this population (5.2 vs. 2.1 months) without any additional toxicity (36). Most patients included in this retrospective analysis received multiple courses of salvage systemic therapies including irinotecan, lomustine, etoposide and bevacizumab prior to SRS. Another prospective trial found that a small cohort of patients tolerated concurrent bevacizumab with SRS (42). The impact of other systemic therapies is difficult to deduce as many included studies were retrospective in nature and the included patient population received multiple agents (36,43-46).
Cho et al. compared SRS and FSRT in recurrent HGG retrospectively and found that the two treatments yielded comparable survival. Although this was a non-randomized study, favorable prognostic factors included smaller tumor volume, younger age, high KPS and lower grade (47). Several other studies found age and performance status to be significantly associated with survival (40,41,45). Two other retrospective reports showed that higher KPS and small tumor volume predicted for increased OS (48).
Time to recurrence may also play a role in predicting OS benefit. One retrospective study reported that longer interval between initial aggressive resection and recurrence correlated with survival (48). Similarly, Maranzano et al. described a potential survival benefit in patients that had adequate time (≥5 months) between initial RT and RT at recurrence (38).
Patel et al. published a retrospective study stating survival was significantly improved in patients who either responded or had stable disease after SRS with median survival of 15.8 vs. 7.3 following radiosurgery (44). Interestingly, it has also been reported that patients treated after 2005 survive longer than those treated prior to this year. Sharma et al. hypothesizes that this could be due to the treatment standardization of GBM patients after the publication of the Stupp protocol or that their institution started prescribing higher median prescription doses to smaller volumes around that time (46).
MGMT promoter methylation status is known to be a favorable prognostic factor in GBM patients. However, only a handful of the included studies documented MGMT status. One study showed a significant median OS benefit in patients with MGMT promoter methylation (33.4 vs. 16 months). However, only 22 patients had MGMT sequencing at the time of this study (41). Another report had 11 patients with MGMT promoter methylation, but did not find a statistically significant difference between OS in the cohort (40). A third study included 15 patients with MGMT sequencing results and only 5 with MGMT promoter methylation. Survival statistics were not provided on this subgroup (46).
Imber et al. reported a trend toward decreased OS in patients in which multiple targets were treated with SRS (37,38). Twenty-one percent of patients in one study had multiple lesions upon recurrence. It is unclear how many of those recurrent lesions were treated with SRS, but their survival was similar to the other studies included in this review. Pinzi et al. did not find any significant OS difference between patients with multiple treated lesions vs. a single lesion (45).
There have been a variety of dose and fractionation regimens used for FSRT treatment in the setting of recurrent high-grade glioma, as detailed in Table 2. In a study comparing the efficacy of SRS versus FSRT in recurrent WHO Grade III and Grade IV tumors, Cho et al. used a median dose of 37.5 Gy in 15 fractions for their FSRT arm (47). Similarly, Minniti et al. evaluated the efficacy of salvage FSRT in combination with TMZ with a dose of 37.5 Gy in 15 fractions (56). Both of these studies represent modestly hypofractionated radiation regimens with 2.5 Gy per fraction. In contrast, a Phase I dose-escalation study investigating FSRT given in combination with gefitinib for recurrent HGG, Schwer et al. were able to deliver 36 Gy in 3 fractions without dose-limiting toxicity (31). In addition, Fields et al. gave 36 Gy in 3 fractions of FSRT in combination with dose-escalated vandetanib in their phase I trial for recurrent malignant glioma. These two trials represent the most aggressively hypofractionated FSRT regimens, with biologically effective dose approaching that of SRS regimens (32). The median dose of the literature surveyed in this review as shown in Table 2 is approximately 35 Gy in 10 fractions, although many trials did allow for dose variation to account for prior radiation dose, proximity to critical structures, and size of the recurrent lesion.
Toxicity remains a concern with FSRT treatment for recurrent high-grade glioma, although perhaps to a lesser degree as compared to SRS, given the normal tissue repair capacity between fractions of radiation. Many of the FSRT studies referenced in Table 2 quoted a zero percent rate of Grade III or higher toxicity. Hudes et al.’s paper aimed to determine the optimal dose of FSRT while decreasing rates of re-operation due to SRS toxicity (30). Shi et al.’s 2018 retrospective review of recurrent HGG patients who progressed on bevacizumab and subsequently received FSRT also noted no treatment-related Grade III or higher toxicity (57). In contrast, a Phase I study investigating the role of combining panobinostat and FSRT reported a 58% rate of Grade III or higher toxicity, although much of this was hematologic and associated with the oral radiosensitizing agent, with only one Grade III RN event (58). In direct comparison studies, such as Cho et al., of FSRT versus SRS—where the confounder of concurrent systemic therapy was not present—toxicity rates as a whole, and particularly radiation necrosis rates, are significantly lower when using FSRT (47).
Both SRS and FSRT have shown efficacy and safety in a variety of different dose and fractionation schedules in recurrent HGG. Further conclusions are difficult to delineate as the included studies used varying inclusion criteria, doses, and systemic therapies (concurrent or adjuvant). It is important to note that the majority of the included studies did not comment on MGMT status which is known to impact survival. Most studies included in this review reported toxicity of therapeutic intervention, but few recorded quality of life and neurocognitive changes. Further prospective trials are ongoing and necessary to further elucidate a standard of care for these patients.
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/cco.2020.03.05). WS: Consulting for Novocure, Brainlab, and Varian. Research funding from Regeneron, Brainlab, Novocure. The other authors have no conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
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