Glioblastoma, a highly aggressive form of brain cancer, requires prompt and accurate diagnosis to initiate effective treatment strategies. The current standard of care for newly diagnosed glioblastoma focuses on a multimodal approach involving surgery, radiotherapy, and chemotherapy, particularly for patients under the age of 70. This comprehensive strategy aims to extend survival and improve the quality of life for individuals facing this challenging condition.
For patients younger than 70 years, the established standard of care combines radiotherapy (RT) with adjuvant temozolomide. This protocol, validated by a significant phase III clinical trial [60], has demonstrated a notable improvement in overall survival rates. Radiotherapy is typically administered over a six-week period, delivering a total dose of 60 grays to the tumor site. Concurrently, temozolomide, an alkylating chemotherapy agent, is given daily during radiotherapy. Following the completion of radiotherapy, patients undergo six cycles of adjuvant temozolomide, administered for five consecutive days each month.
However, the presence or absence of hypermethylation in the MGMT promoter region [61] significantly impacts the prognosis and the effectiveness of temozolomide. Specifically, the absence of MGMT promoter hypermethylation is associated with a poorer prognosis and reduced efficacy of temozolomide. Despite this factor, the treatment protocol pioneered by Stupp and colleagues has shown a significant advancement in patient outcomes. Using this combined approach, the average survival rate increases from 12.1 months with radiotherapy alone to 14.6 months. Furthermore, the two-year survival rate sees a substantial improvement, rising from 8% to 26% with the addition of concomitant temozolomide [60]. It is important to note that this pivotal trial primarily included patients younger than 70 years of age.
In the older patient population, specifically those over 70, the standard of care adapts to consider patient frailty and tolerance. Hypofractionated radiotherapy, often combined with temozolomide [62] when appropriate, forms the basis of treatment. The feasibility and intensity of treatment are carefully tailored to the individual patient’s general health and functional status. Even radiotherapy alone (at a dose of 54 grays) has been shown to offer a survival benefit in older patients, extending survival to 29.1 weeks compared to 16.9 weeks with supportive care alone, without compromising quality of life [63]. These positive outcomes have been confirmed in patients with a Karnofsky performance status (KPS) score greater than 60 [64]. Recent studies have further indicated that a shorter course of radiotherapy combined with temozolomide can lead to improved survival (9.3 months versus 7.6 months) in older patients (over 65 years).
A randomized trial by Malmstrom et al. [65] focused on patients aged 60 and older with glioblastoma to determine the optimal palliative treatment strategies. The findings revealed that radiotherapy alone results in poorer outcomes in this age group. Conversely, both temozolomide and hypofractionated radiotherapy emerged as standard treatment options, particularly beneficial for patients exhibiting methylation of the MGMT gene promoter. For patients in poor general health, supportive care may be the most appropriate approach, prioritizing quality of life and minimizing hospital stays [62].
Monitoring for disease progression is crucial and is typically performed using brain MRI scans every 2 to 3 months, guided by the Response Assessment in Neuro-Oncology (RANO) criteria [66]. Upon recurrence of glioblastoma, a standardized treatment approach is lacking. Treatment decisions at this stage are heavily influenced by the patient’s overall condition and prior treatments [67]. A second surgical resection may be considered for younger, fitter patients with a preserved KPS. This strategy has been linked to prolonged survival in carefully selected patients [68], demonstrating an increase in median overall survival (22 months versus 14 months in patients without second surgery at recurrence). Importantly, a significant majority (80%) of patients did not require rehabilitation following a second surgery.
In specific cases, intracavitary carmustine wafers (BCNU) may be utilized during the initial surgery or at recurrence [69]. However, the efficacy and potential side effects of this therapy remain under ongoing investigation and debate [70,71]. When surgical resection is not feasible, second-line chemotherapy options may include nitrosoureas, temozolomide, or antiangiogenic agents like bevacizumab. Unfortunately, these options have not yet demonstrated clear benefits in terms of significantly improved survival rates [72], with overall survival from recurrence averaging approximately 6 months [73].
Given the generally poor prognosis associated with glioblastoma, the development of novel therapeutic strategies is urgently needed. The REGOMA trial (Regorafenib in Relapsed Glioblastoma) [74] represents a phase II randomized trial exploring the use of regorafenib, an inhibitor targeting angiogenic and oncogenic receptor tyrosine kinases, at glioblastoma recurrence. The preliminary results have shown some promise in improving overall survival with a manageable side effect profile, paving the way for a potential phase III trial to further evaluate its efficacy.
