Proton therapy is a novel technique that utilizes a heavier particle than standard photons to deliver radiation. Protons therefore enable dose reduction while sparing normal brain tissue during radiation given the lesser exit dose. There is limited data available for the efficacy of protons in adult LGG. Hauswald et al. [21] retrospectively analyzed patients with low-grade glioma (WHO grade I and II) treated with proton therapy. Proton beam therapy was administered to 19 patients total (median age 29). Median dose applied was 54 Gy in fractions of 1.8 Gy. Median follow up was only 5 months; therefore, PFS and OS data are incomplete. The treatment was tolerable with the most common complication of focal alopecia and fatigue. Further prospective trials with extended follow up are needed to determine the role of proton therapy in LGG treatment.

Much of the data for chemotherapy use in LGG has been extrapolated from data on the treatment of high-grade glioma (HGG). There is substantial overlap in the chemotherapeutic regimens utilized in HGG and LGG, which are most commonly TMZ and procarbazine/lomustine (CCNU)/vincristine (PCV). Chemotherapy can be given during radiation, adjuvantly following radiation treatment, or at progression. There is still controversy over the ideal chemotherapy agent, the ideal time of administration, and the optimal duration of chemotherapy treatment. Recent data suggests that chemotherapy can play a role in improving outcome of LGG patients (Table 1).

As the use of TMZ has become standard of care for HGG [22], its use in LGG has increased among the neurooncology community. Prior to the widespread use of TMZ, PCV was the chemotherapy of choice for gliomas and in long-term analysis of prior studies, PCV may still have superior survival outcomes specifically in codeleted gliomas [23]. However, part of this regimen requires intravenous administration and can produce significant hematopoietic toxicity for patients. TMZ is usually better tolerated and easier to administer compared to PCV. The efficacy of TMZ has never been compared head-to-head with PCV in a prospective, randomized trial.

The largest trial evaluating long-term benefit from chemotherapy in upfront LGG is the Radiation Therapy Oncology Group (RTOG) 9802 trial. In this study, a total of 251 patients with LGG were enrolled and divided into high-risk and low-risk LGG. Patients with favorable risk included those less than 40 years old and those with gross-total resection. Unfavorable risk patients were those over 40 years with STR or biopsy only. Patients in the favorable risk group were observed postoperatively. Patients in the unfavorable risk group were randomly assigned to RT alone or RT followed by PCV chemotherapy. A significant improvement in OS was noted for study participants who received PCV chemotherapy plus radiation (13.3 years median survival time) compared to those receiving radiation therapy alone (7.8 years median survival time) [24, 25]. This was similar to results seen in patients with grade III anaplastic oligodendroglioma and oligoastrocytoma who also showed improved response to treatment with PCV chemotherapy [26]. In addition, chromosome 1p/19q deletions have been associated with favorable radiographic response rates and prolonged survival in patients with anaplastic oligodendrogliomas receiving PCV therapy [27]. Loss of the heterozygosity of chromosomes 1p and 19q have been shown to be powerful predictors of survival and chemosensitivity in grade 3 oligodendroglial tumors [28] and presumably have the same prognostic and predictive impact in their LGG counterparts.

RTOG 9802 trial showed efficacy of chemotherapy in conjunction with RT. However, optimal timing of chemotherapy relative to radiation is unclear as is the best choice of chemotherapy. One study utilized neoadjuvant PCV in large unresectable low-grade gliomas or gliomatosis cerebri to avoid large field radiation. The median time to disease progression in newly diagnosed patients was >24 months [29]. Another RTOG trial (RTOG 0424) recruited high-risk LGG patients at upfront diagnosis for treatment consisting of concurrent radiation (54 Gy/30 fractions) and TMZ 75 mg/m² followed by 12 adjuvant cycles of TMZ 150–200 mg/m² for 5 days. Preliminary results are available. 136 patients were accrued. Median follow-up time is 4.1 years. Median survival time has not yet been reached. Three-year OS rate was 73.1 %, significantly improved from historical controls. Long-term data from this trial is still pending [30].

Multiple trials have evaluated TMZ in the recurrent LGG setting and have showed disease response. Pace et al. [28] prospectively examined 43 patients with LGG who were treated with TMZ (5 day on/23 off at a dose of 150–200 mg/m²/day for 5 days per month) at the time of documented clinical and radiological progression. Median duration of response was 10 months with a PFS rate of 39 % at 12 months. Quinn et al. [31] conducted a phase II trial of TMZ (5 day on/23 off at a dose of 200 mg/m²) for 46 patients with progressive low-grade glioma. The objective response rate was 61 %. Median PFS was 22 months. And lastly, Hoang-Xuan et al. [27] conducted a third prospective study of 60 patients with LGG and progressive disease on MRI treated with TMZ (5 day on/23 off at a dose of 200 mg/m²) where objective radiologic response was 31 % and the median time to maximal tumor response was 12 months. Overall, there was a statistically significant positive correlation seen with the loss of chromosome 1p (with or without 19q deletion) and radiographic response to treatment. Retrospectively, Kaloshi et al. [10] examined 149 patients treated with TMZ (5 day on/23 off at a dose of 200 mg/m²) in which 53 % experienced an objective response. The median time to maximal response was 12 months. The median PFS was 28 months. Combined 1p/19q codeletion was associated with a higher rate of response, longer PFS, and longer OS. All of the above studies utilizing TMZ in LGG treated patients with 10–14 cycles of monthly TMZ. In LGGs treated with TMZ, it has been suggested that prolonged duration of treatment (aka metronomic or dose-dense therapy) may achieve a prolonged response. Similar to their HGG counterparts, the methylation status of LGG may impact its response to TMZ as well [32, 33]. Metronomic TMZ has been tried in the LGG setting with the goal to overcome MGMT resistance in patients with newly diagnosed LGG. Kesari et al. [2, 34] looked at patients with LGG who received TMZ dosed at 75 mg/m² daily for 7 weeks followed by 4 weeks off treatment (11 week cycle). Treatment continued for a total of six cycles or until tumor progression and overall median PFS was 38 months. Molecular analysis revealed that patients who had a methylated MGMT promoter or deletion of either 1p or 19q chromosomes had longer OS. In LGG, dose-dense TMZ has not been compared to the conventional 5 day on/23 off regimen. However, in GBM patients, metronomic TMZ has been compared to the conventional “Stupp” regimen in the RTOG 0525 study which showed a lack of increased efficacy with dose-dense TMZ and increased toxicity for patients [35]. With the available data, the authors recommend using traditionally dosed adjuvant TMZ when indicated for 6–12 cycles.