Efficacy
Surgery alone is not associated with long term control for the majority of patients with low-grade glioma (LGG) and adjuvant treatment improves this. The timing of radiation therapy (RT) in the management of LGG remains a contentious issue. Patient outcomes vary according to prognostic factors, with immediate RT advocated for selected patients based on individual risk factors. The decision between immediate or delayed treatment should be individualised and consider the risk status of the patient. When there is a decision to initiate treatment, this should be RT followed by chemotherapy.
The EORTC 22845 study investigated the use of early RT (RT immediately after surgery) vs. delayed RT on progression of the disease after surgery (observed group).r In the study, 311 patients were randomised to early RT (54 Gy in 30 fractions) or observation with delayed RT at progression. At 5 years, progression free survival (PFS) favoured the early RT group when compared to the observed group, 55% (95% CI:46.7%-63.3%) vs. 35% respectively. Median PFS was 5.3 years (early RT) compared with 3.4 years (observed). There was no significant difference in OS noted between either treatment groups, 7.4 years (early RT) vs. 7.2 years (observed). At one year follow-up there were significantly less seizures in the patients who had received RT (25%) compared to the patients who had not (41%).
Figure 1: PFS by intention-to-treat analysis
© Lancet 2005r
Optimal radiation therapy dose
The optimal total dose for LGG RT has been established as 50.4-54 Gy by two randomised control trials (RCT): EORTC 22844 and the intergroup study NCCTG-RTOG-ECOG.rr
The EORTC 22844 trial randomised 379 adult patients with cerebral LGG to receive post-operative (or post-biopsy) RT with either 45 Gy in 25 fractions (five weeks) or 59.4 Gy in 33 fractions (6.6 weeks).r After a median follow-up of 74 months there was no significant difference between the 45 Gy and 59.4 Gy arms in terms of survival (58% and 59% respectively) or PFS (47% and 50% respectively).
The Intergroup RCT (NCCTG-RTOG-ECOG) study randomised 203 patients with LGG to receive either 50.4 Gy in 28 fractions or 64.8 Gy in 35 fractions.r No benefit in five year OS was demonstrated between 50.4 Gy (72%) and 64.8 Gy (64%). The higher dose arm was associated with worse neurotoxicity, and when comparing the 50.4 Gy to 64.8 Gy the 2 year incidence of radiation necrosis was 2.5% vs 5% respectively.
Role of chemotherapy
The role of chemotherapy in the management of LGG is evolving. The updated results of the phase III RTOG 9802 and other phase II trials have reported chemotherapy responses in LGG when used as adjuvant therapy and for progressive disease.r Response rates of 50-60% have been reported with procarbazine, lomustine and vincristine (PCV), and temozolomide (TMZ).
RTOG 9802 randomised 251 high risk LGG patients to RT alone (54 Gy in 30 fractions) or RT followed by six standard cycles of PCV chemotherapy.r At a median follow up of 11.9 years, the combination of RT and chemotherapy had a longer median survival than patients who received RT alone (13.3 vs. 7.8 years, HR 0.50, p = 0.003).r Median PFS was also improved to 10.4 years among patients that received RT plus chemotherapy compared to four years among patients that received RT alone. The separation of survival curves did not occur until approximately three years post randomisation. Grade 3 and 4 haematological toxicity was greater in the RT plus chemotherapy arm.
Figure 2: OS according to treatment group
© N Engl J Med 2016r
It is unclear if TMZ is as effective as PCV chemotherapy as there are no trials comparing these regimens. The phase II RTOG 0424 has shown that for high risk LGGs treated with concurrent RT (54 Gy in 30 fractions) and daily TMZ followed by monthly TMZ, the three year OS rate of 73.1% was higher than reported historical controls.r
The EORTC 22033 study randomised 477 patients with high risk LGG to receive either 12 cycles of TMZ (75 mg/m2 for 21 days out of 28) or 50.4 Gy of RT.r Patients were stratified for 1p status (deleted, non-deleted or indeterminate) and treated at clinical or MRI progression. Markers for 19q status were later tested but not used for stratification. With a median follow up of four years, there was no difference in median PFS between the two groups (39 months in the TMZ group vs 46 months in the RT group). The PFS results in both arms are inferior to those of the combined modality arm of the RTOG 9802 trial, where RT and PCV were used.r In the subset of IDH mutant, 1p/19q non-co-deleted patients, PFS was longer in those receiving RT than those receiving TMZ. In the IDH mutant, 1p/19q co-deleted patients, PFS was similar for both arms. There was no difference in HR-QoL or mini mental state examination at 36 months in either group. The role of adjuvant chemotherapy with TMZ in place of adjuvant RT still requires long term data, as the median OS in this patient population was not yet reached at the time of publication of the study.
Vorasidenib, a dual mutant IDH1/2 enzyme inhibitor, has been shown to improve progression free survival and increase time to next intervention, compared with observation alone in patients with residual or recurrent grade 2 IDH-mutant glioma.r The median PFS was 27.7 months in patients treated with Vorasidenib and 11.1 months in those treated with placebo.