Age Alone is Not an Indication for Chemoradiotherapy in Lower-Grade Gliomas

Age should not be considered an indication for administration or deferral of adjuvant treatment in the absence of additional clinical or molecular risk factors for patients with lower-grade gliomas, according to a retrospective cohort analysis published in the Journal of Clinical Oncology.

Among 1499 patients with primary, treatment-naïve nonglioblastoma lower-grade gliomas in the PROGRES cohort, the 5-year progression-free survival (PFS) rate was 47% in patients 40 years and older vs 56% in patients younger than 40 years (HR, 1.21; 95% CI, 1.05-1.39; P = .007). The median follow-up time for living patients was 79 months (IQR, 39-115), and 850 progression events and 610 deaths had occurred.

Among patients with IDH wild-type status, those with an age of 40 years or greater had a 5-year PFS rate of 6% vs 24% in those younger than 40 (HR, 1.74; 95% CI, 1.21-2.50; P = .003). In IDH mutant glioma, the 5-year PFS rate was 60% vs 59%, respectively (HR, 0.89; 95% CI, 0.76-1.05; P = .22). The investigators noted that there was a significant interaction between age and IDH status (P_interaction <.001). When age was analyzed as a continuous variable, every year increased the risk of progression by 1.2% for patients with IDH wild-type disease (HR, 1.012; 95% CI, 1.002-1.022; P = .01) and –0.2% for patients with IDH-mutant glioma (HR, 0.998; 95% CI, 0.992-1.005; P = .65; P_interaction <.001).

In the IDH wildtype group, those between the ages 40 and 59 had a 5-year PFS rate 17% vs 50% in those 18 to 39 years (HR, 2.44; 95% CI, 1.60-3.72; P <.001). In the IDH mutant group, the 5-year PFS rates were 81% vs 82%, respectively (HR, 1.12; 95% CI, 0.91-1.39; P = .25; P_interaction <.001).

Regarding additional molecular risk factors, CDKN2A/B homozygous deletion was noted in 6.4% of patients with IDH-mutant/1p19q-intact tumors, and age was not associated with CDKN2A/B homozygous deletion. Among those with IDH wild-type tumors being 40 years or older was associated with molecular features suggestive of more aggressive disease biology. This includes TERT promoter mutation, found in 65% vs 28%, EGFR amplification, found in 42% vs 15%, and chromosome +7/–10 alteration, found in 57% vs 25%.

“In conclusion, our data suggest that age by itself has little relevance for contemporary definitions of lower-grade gliomas compared with other available clinical and histomolecular factors,” wrote lead study author Connor J. Kinslow, MD, of the Department of Radiation Oncology at Memorial Sloan Kettering Cancer Center, with coauthors in the study. “The prognostic effect of age was largely explained by its association with known molecular risk factors.”

This study collected data from the PROGRES database for all cases of nonglioblastoma astrocytomas and oligodendrogliomas with low grade or anaplastic morphology, regardless of IDH status, with an age of 18 years or older and no prior cancer-directed chemotherapy or radiotherapy.

Across those in the PROGRES cohort, patients who were 40 years or older more frequently had grade 3 disease (73% vs 59%) and IDH wildtype tumors (26% vs 9%). They also received radiotherapy (77% vs 61%) and chemotherapy (72% vs 67%) more frequently, in addition to having poorer performance status, defined as World Health Organization score of 1 or lower (41% vs 29%).

The primary end point of the study was PFS for patients aged 18 to 39 years compared with patients aged 40 years or older. OS was a secondary end point.

Study investigators also pooled data from 4 international randomized clinical trials of patients treated with adjuvant radiotherapy or chemoradiotherapy to infer how to modify the effect of adjuvant chemoradiotherapy: the RTOG 9802 study (NCT00003375), the RTOG 9402 study (NCT00002569), the EORTC 26951 study (NCT00002840), and the CODEL study (NCT00887146). Among 344 eligible patients, chemoradiotherapy was associated with improved PFS (HR, 0.42; 95% CI, 0.32-0.54; P <.001) and OS (HR, 0.52; 95% CI, 0.39-0.69; P <.001), and the benefit of chemoradiotherapy was greater in those who received subtotal resection/biopsy compared with gross total resection.

“[A]ge alone should not be considered an indication for chemoradiotherapy in the absence of other clinical or histomolecular risk factors. Practice guidelines should be revised to reflect contemporary prognostic factors in the molecular era,” concluded the study authors.

References

Kinslow CJ, Minniti G, Brown PD, et al. Prognostic and predictive effect of age in molecularly defined lower-grade gliomas. J Clin Oncol. Published online August 12, 2026. doi:10.1200/JCO-25-01846