The indolent natural course of LGGs has resulted in uncertainties and controversies regarding the role, timing, and technique of both surgery and RT. Subjects of debate include more aggressive vs. more limited resection such as biopsy (or even observation), timing of RT as adjuvant therapy immediately after surgery vs. delayed until recurrence, and the role for chemotherapy. Long-term follow-up is paramount to make such evaluations of PFS and OS. With a median follow-up of 13.6 years, the current study is among the largest with such long-term follow-up. Additionally, this study is unique in accomplishing a separate analysis of patients undergoing STR and biopsy alone. outlines data from the present series alongside results of the European Organisation for Research and Treatment of Cancer (EORTC) protocol 22845 and other randomized trials.2–5
Results of low-grade glioma randomized trials and present series
Surgery at the time of diagnosis provides tissue diagnosis in addition to a potential therapeutic debulking benefit. Similar to other investigations, our study displayed improved outcomes for patients who underwent more aggressive resections. However, GTR is often not possible without serious risk of neurologic injury because of tumor location or infiltration. We found that aggressive resections were more likely to have been performed in patients with more favorable tumor characteristics, such as size smaller than 5 cm, lack of enhancement on CT scan, and lack of sensory motor symptoms. To date, no randomized trials have specifically compared “up-front” surgery with a more conservative approach of delayed surgery. However, considering both retrospective and prospective data, many neurosurgeons favor maximally safe resection.3,4,10,12,16,22,27,29,33
Although not randomized, three prospective studies correlated aggressive surgery (GTR or near GTR) and improved prognosis.3,4,34
Additionally, an intraoperative MRI study found that patients undergoing STR experienced 1.4 and 4.9 times the risk of recurrence and death, respectively, compared with GTR (12). Another recent study, using MRI volumetric analysis, correlated resection of 90% or more with improved OS and PFS (27).
Retrospective data are inconsistent relative to the effect of postoperative RT. Due to perceived toxicities with RT and the disease’s indolent nature,35,36
some advocate delaying RT until there is evidence of progression, symptoms, or high-grade transformation.14,17,37–48
EORTC 22845 evaluated the timing of RT in a phase 3 trial of immediate RT (54 Gy) or observation until progression. With follow-up just over 7 years, postoperative RT significantly prolonged PFS (median, 5.3 vs. 3.4 years) without affecting OS (median, 7.4 vs. 7.2 years).2,5
These results are inconsistent with the present study’s findings of improved OS on multivariate analysis but no impact on PFS for adjuvant RT. In addition, in the present study, the benefit of postoperative RT was most clearly seen, in terms of improved OS and PFS, in patients undergoing more limited resections.
The most likely explanation for differences in PFS outcomes between studies is the imbalance in patient groups who did or did not receive postoperative RT. In the present study, treatment decisions were not randomized, and as noted, RT was preferentially delivered to higher-risk patients, such as those with more aggressive tumors and, most important, after less aggressive resections. The strong effect the extent of resection had on OS and PFS in this study likely confounds the PFS data. An alternate interpretation of the current data is that RT can improve outcomes in high-risk patients to approximate the PFS outcomes seen in more favorable risk categories. The differences in OS outcomes between the studies may be attributable to the significantly longer follow-up in this study than in EORTC 22845 (13.6 vs. 7.7 years). Furthermore, in the EORTC trial, 44% of patients underwent GTR (>90% resection), a much higher percentage than in this report, where only 23% of patients underwent GTR/rSTR. In light of our findings, it is therefore possible that the EORTC trial was not able to show a survival benefit because it included a large percentage of patients at lower risk of progression and death who were less likely to benefit from RT. This is further supported by the current results in which the patients who underwent more limited resections benefited most, in terms of OS and PFS, from postoperative RT ().
Because diagnostic and surgical techniques evolved over the period of the present evaluation, and in order to offer a more relevant comparison to the modernera EORTC and NCCTG trials (which both began enrolling patients in 1986), we analyzed the present data of the 95 patients (30%) who presented in 1986 or later. Median follow-up in this group was 12 years. Patients who presented in 1986 or later, compared with patients who presented before 1986, had improved OS (median, 9.2 vs. 6 years; p = .02) but not PFS (median, 5.3 vs. 4.4 years; p = .17). Of these 95 patients, 24 (25%) underwent GTR/rSTR. Similarly, of the 219 patients whose disease was diagnosed before 1986, 49 (22%) underwent GTR/rSTS. Therefore, it does not seem likely that the extent of surgical resection varied on the basis of decade of presentation when the EORTC and NCCTG trials’ time frames are used. Similar to the results of the entire study cohort, the extent of resection was strongly predictive of both OS and PFS in the cohort of patients whose disease was diagnosed in 1986 or later (univariate analysis data not shown). Use of RT was not associated with either OS or PFS in this modern cohort (univariate analysis data not shown). For the 71 patients whose disease was diagnosed in 1986 or later and who underwent more limited surgical procedures (biopsy/STR), postoperative RT showed a trend toward PFS on univariate analysis (5-year PFS, 51% vs. 13%; 10-year PFS, 21% vs. 11%). However, this difference was not statistically significant (p = .18). The use of postoperative RT was not associated with improved OS (p = .65) in this subgroup.
The disparity in these results, compared with those for the whole group, may be attributed to insufficient follow-up and patient numbers to detect a statistical difference. Furthermore, even though a similar percentage of patients underwent GTR/rSTR, improvements in imaging and surgical techniques that allow for earlier detection, more aggressive yet safe resection, and more accurate classification of surgical extent could certainly be affecting the data. Also, the limitations of referral bias are likely to be even more pronounced in the modern series with more high-risk patients being referred for RT. Because the OS in the more modern group is improved and extent of surgery is the strongest predictor for survival in our series, it is likely that all these factors contribute to the differences in results. Overall, the data presented herein from the subset of more modern patients are not unlike the findings of the EORTC trial for which postoperative RT showed improved PFS2,5
but no improvement in OS.
A minority of patients received chemotherapy at the time of diagnosis, combined with RT in only 5%, and 1% received chemotherapy alone. Chemotherapy was much more frequently given to patients at the time of recurrence (48% of recurrences). No strong evidence exists for routine use of postoperative chemotherapy, especially in light of two phase 3 trials that showed no significant improvement in OS or PFS.34,49
Temozolomide is a promising oral alkylating agent with proven benefit in high-grade gliomas.50,51
Thus, temozolomide has been used in some small trials to delay RT in patients with newly diagnosed LGG.52,53
Ongoing trials by the EORTC, the Eastern Cooperative Oncology Group, and the Radiation Therapy Oncology Group will evaluate temozolomide’s role for those deemed at high risk for early progression. Until these results are known, the current findings suggest careful consideration for the use of temozolomide as a means of delaying RT because it may have a detrimental effect on PFS and OS, especially in patients with minimal surgical resection.
In summary, analysis of a large series of patients with nonpilocytic WHO grade II LGG with long-term follow-up from a single institution indicates that for the majority of patients prognosis is poor (15-year OS 23%), especially recognizing that these patients are frequently young adults. However, there are subsets of patients who do significantly better, such as those undergoing an aggressive surgical resection. Our results favor performing a maximally safe resection, and in patients who have undergone STR/biopsy alone, we favor early use of RT, given the observed benefits in OS and PFS.