Table 2.
Summaries studies regarding adjuvant therapy in Low-grade gliomas (LGG)
| Study | Design | Inclusion criteria | Treatment protocol | Results and comments |
|---|---|---|---|---|
| Observation (wait and see) | ||||
| RTOG 9802 (Shaw EG. J Neurosurg 2008) [13] | Phase II (n = 111) | Age < 40 years Gross Tumor resection |
No adjuvant therapy | OS rates at 2 and 5 years were: 99 and 93%, respectively. PFS rate at 5 year: 48% In patients without unfavorable prognostic factorsa, 2- and 5-year PFS rates were 100 and 70%., respectively. |
| Adjuvant radiotherapy | ||||
| EORTC 22845/MRC BR04 (Karim AB. Int J Radiat Oncol Biol Phys 2002) [17] | Phase III (n = 290) | Low-grade astrocytoma, oligodendroglioma, and mixed oligoastrocytomas | Early RT (54 Gy) versus No postoperative RT |
Early RT showed an improvement in TTP (4.8 versus 3.4 years; p = 0.02). HR = 0.68 (95% CI 0.50–0.94). No differences in OS: HR = 1.15 (95% CI 0.67–1.74). The 5-year OS rate were: 63 versus 66% (p = 0.49). |
| EORTC 22845 (Van den Bent MJ. Lancet 2005) [16] | Phase III (n = 311) | WHO grade II or pilocytic astrocytomas with incomplete resection | RT (54 Gy) after biopsy or initial resection, versus No RT until progression |
Early RT was associated with an improvement PFS (5.3 versus 3.4 years): HR = 0.59; 95% CI 0.45–0.77 (p = 0.0001). No difference in OS (7.4 versus 7.2 years): HR = 0.97; 95% CI 0.71–1.34 8 (p = 0.872) Seizure control also improved in patients treated with early radiotherapy. |
| EORTC 22844 (Karim AB. Int J Radiat Oncol Biol Phys 1996) [19] | Phase III (n = 379) | Low-grade astrocytomas (Gl and G2), oligodendrogliomas, and mixed oligoastrocytomas | Surgery + low dose RT (45 Gy) versus Surgery + high dose RT (59.4 Gy) | No significant difference in the 5-years OS between low-dose arm (58%) and high dose arm (59%). No significant difference in the 5-years PFS (47% verss 50%) |
| NCCTG/RTOG/ECOG (Shaw EG. J Clin Oncol. 2002) [18] | Phase III (n = 203) | WHO grade II gliomas | Surgery + low dose RT (50.4 Gy) versus Surgery + high dose RT (64.8 Gy) | No differences in 2- and 5-year OS between low dose (94 and 75%) and high dose arm (85 and 64%) (p = 0.48) Patients treated with high doses showed higher rates of severe radionecrosis (5 versus 2.5%) |
| Adjuvant radiotherapy and chemotherapy | ||||
| RTOG 9802 trial (Buckner JC. N Engl J Med. 2016) [21] | Phase III (n = 251) | High-risk LGG: Age ≥ 40 years and/or subtotal resection |
Postoperative RT (54 Gy) versus Postoperative RT (54 Gy) plus 6 cycles of adjuvant PCV |
Post-RT + PCV conferring a survival advantage over RT alone: median OS 13.3 versus 7.8 years (HR: 0.59; 95% CI 0.42–0.83; p = 0.003). Median PFS was prolonged in patients who received PCV (10.4 versus 4.0 years): HR: 0.50; 95% CI 0.36–0.68 (p < 0.001) |
| RTOG 0424 (Fisher BJ. J Radiat Oncol Biol Phys. 2015) [23] | Phase II (n = 129) | LGG with ≥ 3 risk factors for recurrence (age ≥ 40 years, astrocytoma histology, bihemispheric tumor, tumor diameter > 6 cm, neurologic function status > 1) | Concurrent radiation (54 Gy) with daily temozolomide followed by monthly temozolomide | The 3-year OS rate was 73% (95% CI 65.3–80.8%), significantly higher than the historical control OS rate of 54% (p < 0.001). The 5-year OS rate was 57.1% (95% CI 47.7–66.5%), and the median OS has not yet been reached. The 3-year PFS was 59.2% (95% CI 50.7–67.8%) and median PFS was 4.5 years (95% CI 3.5–NA). |
| Chemotherapy alone with deferred radiotherapy | ||||
| EORTC 22033–26033 (Baumert BG. Lancet Oncol. 2016) [24] | Phase III (n = 477) stratified by 1p status |
LGG with at least one high-risk feature (aged > 40 years, progressive disease, tumour size > 5 cm, tumour crossing the midline, or neurological symptoms) | RT (up to 50.4 Gy versus Dose-dense oral TMZ (75 mg/m2 once daily for 21 days, repeated every 28 days, for a maximum of 12 cycles) |
There was no significant difference in PFS between TMZ group (39 months) and RT group (46 months): HR: 1.16; 95% CI 0.9–1.5 (p = 0.22). Median OS has not been reached. Better PFS in IDH-mutant, non-codeleted patients treated with radiotherapy: 55 versus 36 months. HR 1.86; 95% CI 1.21–2.87 (p = 0.0043) |
| Wahl M, et al. (Neuro Oncol. 2017) [27] | Phase II (n = 125) | LGG and gross residual disease | Monthly cycles of TMZ for up to 1 year or until disease progression | The median PFS and OS were 4.2 and 9.7 years, respectively. Patients with 1p/19q codeletion demonstrated a 0% risk of progression during treatment |
LGG: low grade gliomas (WHO grade II astrocytoma, oligodendroglioma or mixed oligoastrocytoma)
RTOG Radiation Therapy Oncology Group, EORTC European Organization for Research and Treatment of Cancer, MRC Medical Research Council, NCCTG North Central Cancer Treatment Group, ECOG Eastern Cooperative Oncology Group study, OS overall survival, PFS progression-free survival, TTP time to progression, RT radiotherapy, PCV procarbazine, lomustine, and vincristine, TMZ Temozolomide
aUnfavorable prognostic factors in RTOG 9802 study: tumour size ≥ 4 cm, astrocytoma or oligoastrocytoma histology, and residual disease ≥ 1 cm. RT: radiotherapy