There are many approaches currently available for the salvage treatment of patients with recurrent HGG after initial RT, including resection, re-irradiation, or systemic agents, but no standard of care exists. Prognosis is grim in this patient population; therefore, assessment of toxicity and quality of life, when considering treatment options, is critical.
The role of chemotherapy at recurrence is unclear and has resulted in a MST from recurrence of 7.5 months.16,17
Bevacizumab is US Food and Drug Administration approved for the treatment of recurrent GBM, with phase II trials indicating prolonged 6-month progression-free and overall survivals.18
Fractionated stereotactic RT is advantageous in treating recurrent, previously irradiated, tumors, particularly when located in eloquent areas, as it allows the therapeutic dose to be delivered over a number of fractions, while minimizing normal tissue toxicity. The largest series of re-irradiation of recurrent gliomas examined the efficacy of 36 Gy delivered in 2-Gy fractions in 172 patients, of which 111 had high-grade gliomas.19
This regimen was well tolerated and resulted in modest survival.
Although the role of chemotherapy combined with RT has been well established for patients with newly diagnosed primary GBM,2,20
there is a paucity of data reporting on the combination of chemotherapy and RT for recurrent gliomas.21–23
Combs et al24
examined the combination of temozolomide with fractionated re-irradiation in 25 patients with recurrent gliomas. The treatment was well tolerated, and MST from retreatment was 8 months. Their results corroborate ours, with no difference noted between temozolomide-naïve patients and patients previously exposed to temozolomide, and no statistically significant benefit to pre–re-irradiation resection. Other studies combining re-irradiation with chemotherapy have demonstrated similar results.25–28
Although it was not a randomized trial, our study did not demonstrate a survival advantage in combining chemotherapy with H-SRT at recurrence compared with patients who received H-SRT alone.
Some chemotherapy agents have shown comparable results to RT alone but with increased toxicity compared with the minimal toxicity noted in our patient population. For example, survival times at progression comparable to H-SRT have been reported with bevacizumab alone but with associated adverse effects of hypertension and thromboembolic events as well as the inconvenience and cost of maintenance therapy. The results are, however, promising, and it may be that finding the appropriate sequence with which to deliver these therapies may lead to longer overall survival times.
Literature is sparse regarding the toxicity or efficacy of H-SRT in this setting of re-irradiating progressive high-grade gliomas.29
H-SRT is an outpatient-based, noninvasive approach that takes advantage of the stereotactic precision as well as the properties of a standard fractionation schedule but is able to shorten the number of weeks of treatment. This is not only more beneficial to patients with respect to quality of life and convenience but also may represent a decrease in cost associated with retreatment. Although the cost of re-irradiation is already a fraction of the cost of systemic maintenance therapy, examination of Medicare reimbursement rates for H-SRT demonstrated a cost savings of 20% (ie, $4,498.07 compared with $5,705.47) with 10 treatments compared with the 18 treatments of a typical fractionation schedule.
Previous studies looking at small populations treated with H-SRT have reported higher rates of necrosis but have utilized a wide range of doses. An association has been noted between higher rates of re-operation and doses greater than 40 Gy.30,31
Of note, the 5- to 6-Gy fractions used in these studies are significantly larger than the 3.5-Gy fractions used in our patient population. Certainly, higher doses per fraction are noted to be associated with increased long-term toxicity in late responding tissue in other disease sites.
In contrast to prior reports of re-operation rates for SRS, brachytherapy, and other H-SRT fractionation schemes,5–8,10–12,23,29–37
all patients who underwent surgical resection after H-SRT demonstrated radiographic progression confirmed by pathology, indicating these patients underwent re-operation because of tumor progression rather than treatment-related effects. Our initial experience with H-SRT used 3.5-Gy fractions to 35 Gy and reported no grade 3 toxicities or re-operation secondary to toxicity, providing additional support that this dose and fraction size is well tolerated.29
Our data suggest that higher doses of H-SRT result in an improved survival; yet, doses greater than 40 Gy have been associated with increased toxicity, indicating the small therapeutic window.
There is currently no consensus regarding the appropriateness of salvage irradiation in patients who experience recurrence shortly after initial treatment. Grosu et al38
examined 44 patients with recurrent HGG and found the most important prognostic factor associated with improved survival after re-irradiation was an increased interval between initial diagnosis and recurrence. In contrast to this, Mayer and Sminia39
reviewed 10 years of re-irradiation studies and did not find a correlation between the time interval from the initial therapy and re-irradiation and improved prognosis.
Our study did not demonstrate an inferior survival from H-SRT in patients who experienced recurrence within 6 months of original treatment. It may be that the larger number of patients examined in our study allowed us to more accurately assess this phenomenon. This finding is of critical importance, as, currently, eligibility to clinical trials is often limited to patients who have survived at least 6 months from initial treatment.
Our patient population was uniform with respect to the technique, dose, and fractionation of RT but differed with respect to time to progression; use of chemotherapy, either with initial treatment or with H-SRT; or use of pre-H-SRT resection. Despite this variability, we observed that all groups of patients benefited similarly from H-SRT, achieving a uniform MST of 11 months. This is comparable to the best reported results in the literature with systemic agents but with an improved toxicity profile, suggesting that H-SRT should be considered standard salvage therapy for previously irradiated HGGs. We noted that patients who experienced recurrence within 6 months after initial treatment had an unexpectedly good prognosis, suggesting they should not be disqualified from H-SRT or other salvage therapy.
In conclusion, we have demonstrated that H-SRT was associated with favorable survival benefit independent of re-operation or concomitant chemotherapy and was well tolerated with minimal adverse effects in patients with recurrent HGG. This study represents, to our knowledge, the largest series to examine the efficacy and tolerability of salvage H-SRT as well as the role of resection and/or chemotherapy combined with H-SRT for HGG. Survival results are comparable to the best-reported results in the literature examining systemic agents (ie, bevacizumab) but with an improved toxicity profile and decreased cost compared with that of systemic maintenance therapy. These results warrant a prospective evaluation of H-SRT in future studies as standard salvage therapy for previously irradiated HGGs.