While complete resection has abundantly been acknowledged as the first line treatment of SEGA, complete and safe surgical removal can be problematic (24, 25). This is perhaps best illustrated by epidemiological studies that provide an unbiased view on real-life efficiency, safety and cost of treatment. A study looking at three large US national healthcare claims databases examined the outcomes of SEGA surgery among TSC patients who underwent SEGA surgery between 2000 and 2009 (26). In 48.9% of the patients postoperative complications were registered. The postoperative diagnosis of 'SEGA' in 100% of the cases and high reoperation rates suggests that many patients had incomplete resection, regrowth or contralateral regrowth. The authors concluded that alternative therapeutic strategies should be considered. Even when safe and complete removal is possible, the tissue damage that is inevitable in surgery, especially for bilateral deep-seated tumors, may lead to neurocognitive decline that could negate part of the positive neurocognitive effects of mass reduction and resolution or prevention of hydrocephalus.
Because of problems associated with surgery as first-line treatment for SEGA, the discovery of activity of the immunosuppressive drug everolimus against SEGA (published in 2006, (27)) was met with considerable enthusiasm. Within 6 years a multicenter randomized trial was published demonstrating that at least 35% of the patients had a 50% or more reduction in SEGA volume after 2y of treatment (5). In a subsequent report of the same patient cohort that received at least one dose of everolimus either initially or after cross-over from the control arm, results and toxicity were reported up to almost 5y of treatment (28, 29). The median change in SEGA volume after 12 months was − 37.8% and this did not improve much, staying below − 50%, during continued treatment (29). This somewhat disappointing observation is especially remarkable because 30% of the cases were cross-overs from the placebo arm and thus may still have been in the initial response rather than the extended phase of response to everolimus. In line, the majority of responses occurred within the first few months, the mean time to response was a short 5.32 months and no further responders were counted beyond approximately 2.5 years. Of the 13 patients that progressed, 5 had first responded to treatment. Toxicity was significant with 36% G III and 4.5% G IV serious adverse events ascribed to treatment, leading to discontinuation in 9.9% of patients.
It should be noted that everolimus was developed as an immunosuppressant and appears to have a cytostatic rather than a cytotoxic effect, and that perhaps life-long treatment may be necessary. Indeed, SEGA usually grow back after cessation of everolimus (27, 30, 31) and control of epilepsy may dramatically depend on continuation of the drug (32). Attention to long-term toxicity is justified because of metabolic (dyslipidemia, hypertriglyceridemia) (33, 34), multiple CYP3A4/PgP-mediated drug interactions and immunosuppressive side effects that can be life-threatening (35). While no direct carcinogenic risk of everolimus in the standard 2-y carcinogenicity bioassays could be detected, these assays are known to be unreliable for immunosuppression-associated carcinogenicity (36) and the product monograph of Certican (Novartis Pharmaceuticals Canada Inc), one of the brand names of everolimus, specifically warns for “increased susceptibility to infection and the possible development of malignancies such as lymphoma and skin cancer” (37).
The cost of life-long treatment may be a problem as well, especially in developing countries (38). These concerns have motivated some authors to perform resections to avoid having to continue the drug even during significant and ongoing responses to mTOR inhibitors (38). Others studied dose-reduced maintenance therapy after at least 12 months of standard dosing and concluded that SEGA volumes need to be closely monitored during reduced-dose maintenance everolimus therapy because the majority of SEGA increased in size, and that patients who did not have a significant response to standard doses should not be recommended for dose reduction (39) .
Irradiation, whilst being a standard modality in the treatment of pilocytic astrocytoma historically appears to have been banned from the treatment options in SEGA. We found very little data to support the strong and widespread expert opinion against the use of fractionated stereotactic or indeed, any other form of irradiation in the treatment of SEGA. A single case of radiation-induced glioblastoma after whole brain radiotherapy has been systematically cited as an argument against the use of radiation, even when modern conformal radiation techniques are known to decrease the radiation burden to the healthy brain tissue by several orders of magnitude.
Because TSC patients do not have an a priori increased risk of malignant intracranial tumors there is no theoretical argument to suggest they may be more susceptible to intracranial tumor induction.
It could be argued that highly conformal radiotherapy techniques would not reduce the risk that the SEGA itself might become malignant. Indeed, in G I pilocytic astrocytomas a few cases have been described that are consistent with radiation as a cause of malignant degeneration (40). However, spontaneous malignant transformation has been described as well (41–46) and it is likely that the selection of tumors to receive radiotherapy may have induced an adverse bias. In G II gliomas, it is well-known that in fractionated radiotherapy actually delays malignant transformation. Furthermore, clinically malignant behavior of SEGA itself appears to be exceedingly rare and only three cases have been mentioned in publications, none of them after therapeutic radiation (47–49).
The bilateral SEGA's that we have treated, before everolimus was in use, with FSRT to a dose of 30 × 2 Gy reacted slowly and progressively over a period of 8 years and decreased to 20% of their original volume. Such slow responses are common in in low-grade or benign intracranial tumors, and have previously led to incorrect conclusions about 'radioresistance' of e.g. meningioma.
Remarkably, after the start of everolimus for extracranial manifestations of TSC, rapid acceleration of the volumetric response of the larger SEGA occurred, suggesting that the irradiated SEGA may not have been fully inactivated by radiation and that the response of SEGA to everolimus likely involves different and perhaps complementary mechanisms of cell kill, potentially involving apoptosis, as has been described in in vitro experiments and xenografts (50).
While in our patient radiation was delivered as the initial treatment for SEGA, followed by everolimus, opposite sequencing of these treatments could be more advantageous. First, the response to everolimus appears to be faster than to radiotherapy and could thus be more effective to avoid or perhaps even treat volume-dependent complications such as hydrocephalus. Second, a smaller radiation target would decrease radiation burden to the surrounding healthy brain.
There is abundant data describing radiosensitising effects of mTOR inhibitors on in vitro and in vivo on non-TSC mutated cells. Any radiosensitising effect of mTOR inhibitors is particularly relevant to the question of whether these drugs should be continued or not during consolidation radiotherapy. mTOR inhibitors could potentially be particularly effective radiosensitisers in SEGA but, on the other hand, would likely radiosensitise healthy tissues as well. The mechanism of mTOR radiosensitisation, however, involves enhanced apoptosis that should not increase the risk of induction secondary tumors.
While extremely intriguing, it may be too early to specifically explore the concept of simultaneous mTOR inhibition and irradiation for SEGA, but whether mTOR inhibitors have administered or not during radiotherapy of SEGA should clearly be documented and reported as it may have a significant effect on the optimal dose of radiation.
The dose that we have delivered is higher than the 50-54Gy in 25–30 fractions that would be conventional in other G I gliomas and many other benign tumors. This had at the time been motivated by an anticipated absence of toxicity and by the theoretical reduction of radiosensitivity in TSC due to a potentially activated PI3 K/Akt/mTOR pathway (51). The few published results of non-fractionated SRS that were published later on appear to confirm the somewhat reduced radiosensitivity of SEGA compared to pilocytic astrocytomas. This is in line as well with our own observation of an acceleration of tumor response of the larger SEGA after starting everolimus.