Could Upfront Temozolomide Chemotherapy Postpone the Need for Radiotherapy in Young Patients with High-Risk Low-Grade Gliomas?
Low-grade gliomas (LGGs) are progressive and infiltrating primary brain tumors that pose significant challenges in treatment, particularly in young patients. The National Comprehensive Cancer Network (NCCN) guidelines recommend maximum safe resection followed by radiotherapy and adjuvant chemotherapy for high-risk LGG patients, defined as those under 40 years old with subtotal resection. However, these guidelines do not address whether adjuvant therapy should be initiated immediately after diagnosis. This uncertainty stems from the findings of the RTOG 9802 trial, which showed improved progression-free survival (PFS) and overall survival (OS) with the addition of chemotherapy to radiotherapy. Temozolomide (TMZ) is a first-line chemotherapy agent for LGGs, and the EORTC 22033-26033 trial demonstrated that TMZ chemotherapy did not significantly prolong PFS compared to radiotherapy, with OS outcomes remaining unknown. Furthermore, a 12-year follow-up study revealed that radiotherapy could cause significant treatment-related side effects, such as cognitive dysfunction, particularly in young patients. Given the goal of preserving cognitive function in this population, the immediate use of post-operative radiotherapy is questionable.
To address this issue, an interventional study (NCT02209428) was initiated in 2014 as a prospective, single-arm, open-label trial at Huashan Hospital, Fudan University, in Shanghai, China. The study aimed to investigate whether upfront TMZ chemotherapy could postpone the need for radiotherapy and delay potential cognitive impairments in young patients with high-risk LGGs. The study enrolled patients under 40 years old with subtotally resected tumors in eloquent areas. Chemotherapy was initiated within 2 weeks to 3 months after surgery and consisted of six cycles of metronomic TMZ administered at a dose of 75 mg/m²/day from day 1 to day 21, repeated every 28 days. Patients were followed up with magnetic resonance imaging (MRI) for tumor volume assessment and neuropsychological evaluations. The primary endpoint was the objective response rate (ORR), which included complete response (CR), partial response (PR), and minor response (MR). Secondary endpoints included the intensity of response (IOR), duration of response (DOR), malignant progression-free survival (MPFS), cognitive function outcomes, and the safety of chemotherapy.
The study enrolled 65 patients with a median follow-up of 39.6 months, and 50 patients underwent long-term neuropsychological evaluations. The ORR was 56.9%, comprising 33.9% PR and 23.1% MR, with no CR observed. Stable disease was noted in 3.1% of patients, while 40.0% experienced disease progression. Patients with isocitrate dehydrogenase (IDH) mutations had a significantly higher ORR compared to IDH wild-type patients (64.3% vs. 11.1%, P = 0.004). No significant correlations were found between ORR and other biomarkers, such as 1p/19q codeletion, O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation, alpha-thalassemia mental retardation syndrome X-linked (ATRX) loss, and telomerase reverse transcriptase (TERT) mutation. The IOR was more pronounced in IDH mutant patients compared to IDH wild-type patients (P = 0.023) and in patients with 1p/19q codeletion compared to those without (P = 0.002). No significant differences in IOR were observed for MGMT promoter methylation, ATRX loss, or TERT mutation.
Based on the 2016 World Health Organization (WHO) classification, patients were categorized into IDH-mutant and IDH-wildtype groups. The IDH-mutant group had a significantly longer DOR than the IDH-wildtype group (median DOR, 52.4 vs. 25.8 months; log-rank P = 0.0007). Similarly, the 1p/19q codeletion group had a longer DOR than the 1p/19q retain group (median DOR, 52.4 vs. 37.5 months; log-rank P = 0.049). Histologically, both diffuse astrocytoma, IDH-mutant, and oligodendroglioma, IDH-mutant, and 1p/19q-codeleted patients had longer DORs than diffuse astrocytoma, IDH-wildtype patients (median DOR, 44.5 vs. 25.8 months, P = 0.004; 52.4 vs. 25.8 months, P = 0.0003).
The malignant progression rate was 17.7% for IDH-mutant patients and 44.4% for diffuse astrocytoma, IDH-wildtype patients. Oligodendroglioma, IDH-mutant, and 1p/19q-codeleted patients had a malignant progression rate of 9.1%. Oligodendroglioma, IDH-mutant, and 1p/19q-codeleted patients also had a longer MPFS than diffuse astrocytoma, IDH-wildtype patients (median MPFS, unreached vs. 43.7 months; log-rank P = 0.025). The MPFS for diffuse astrocytoma, IDH-mutant patients was unreached.
The OS follow-up time was not reached, and 26 of 65 patients experienced tumor recurrence. Three patients received a second course of TMZ chemotherapy for six cycles, and their tumors remained stable. Eleven patients received radiotherapy at recurrence, with two patients eventually dying. Eleven patients received radiotherapy and chemotherapy after re-surgery, with four eventual deaths. One patient underwent re-surgery without radio-chemotherapy, and the tumor remained stable.
Cognitive function was assessed at five time points: before chemotherapy, after chemotherapy, 1 year after surgery, 2 years after surgery, and 3 years after surgery. The mean Hopkins Verbal Learning Test-Revised (HVLT-R) scores were 14.5, 17.6, 20.5, 22.4, and 23.9, respectively. Scores at 2 and 3 years after surgery were significantly higher than those at 1 year after surgery and before chemotherapy. Although the mean HVLT-R score at 3 years after surgery was higher than at 2 years, the difference was not statistically significant. The Trail Making Test (TMT) time A and B showed that patients completed the tests in significantly shorter times during follow-up compared to before chemotherapy. The Multilingual Aphasia Examination Controlled Oral Word Association (COWAT) demonstrated statistically significant increases in the number of animal, furniture, and switch naming during follow-up compared to before chemotherapy. The Mini-Mental State Examination (MMSE) scores were 26.8, 28.2, 28.9, 28.7, and 29.1, respectively, with scores at 1, 2, and 3 years after surgery significantly higher than those before and after chemotherapy.
Comparison of cognitive results with historical data from patients undergoing early radiotherapy (NCCTG protocol 86-72-51) showed that cognitive dysfunction was significantly less pronounced after chemotherapy. Additionally, cognitive results of patients receiving chemotherapy alone were compared with those of 11 patients receiving post-operative radiotherapy with or without adjuvant chemotherapy. The results indicated significant improvements in MMSE scores, AVLT/HVLT-R total, and TMT time Part B tests in the chemotherapy-alone group.
TMZ chemotherapy was well-tolerated, with no discontinuations except for one patient who experienced Grade 3 thrombocytopenia. No alkylating agent-related secondary tumors were observed.
The study concluded that IDH mutation and 1p/19q codeletion are associated with better chemotherapy response and prognosis. Upfront TMZ chemotherapy may control tumor progression for 4 years or longer in IDH-mutant patients, potentially postponing the need for radiotherapy and delaying cognitive impairments. For IDH wild-type patients, who have a poorer response and prognosis, early concurrent chemo-radiotherapy may be necessary. The study suggests that upfront TMZ chemotherapy could be considered in biologically favorable groups to preserve cognitive function and delay radiotherapy.
doi.org/10.1097/CM9.0000000000001434
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