Randomized phase III trial of metabolic imaging-guided dose escalation of radio-chemotherapy in patients with newly diagnosed glioblastoma (SPECTRO GLIO trial)
Study Overview
This study investigated the efficacy of magnetic resonance spectroscopic imaging (MRSI)-guided dose escalation in treating patients with newly diagnosed glioblastoma (GBM) (1). The study was designed as a multicentric prospective phase III trial. The population under investigation comprised patients who had undergone biopsy or surgery for GBM.
The intervention under investigation involved two different dosing strategies for radio-chemotherapy. Patients were randomly assigned to either a standard dose (SD) group or a high dose (HD) group. The standard dose was 60 Gy, while the high dose was 60 Gy with an additional simultaneous integrated boost totaling 72 Gy directed at MRSI metabolic abnormalities, the tumor bed, and residual contrast enhancements. Alongside the radiotherapy, Temozolomide was administered concomitantly and continued for 6 months thereafter.
The study did not specify a separate control group; instead, the standard dose group served as a comparative control for the high dose group. The total number of patients included in the study was 180. These patients were enrolled between March 2011 and March 2018.
The results showed that after a median follow-up of 43.9 months, the median overall survival (OS) was 22.6 months in the standard dose group and 22.2 months in the high dose group. The median progression-free survival was 8.6 months in the standard dose group versus 7.8 months in the high dose group. Notably, there was no increase in toxicity rate observed in the high dose group compared to the standard dose group. The pseudoprogression rate was similar across both groups, with 14.4% in the SD group and 16.7% in the HD group. In patients with O(6)-methylguanine-DNA methyltransferase (MGMT) methylated tumors, the median OS was 38 months for the high dose group versus 28.5 months for the standard dose group.
The conclusion drawn from the study was that the additional MRSI-guided irradiation dose totaling 72 Gy was well tolerated but did not result in an improvement in overall survival for patients with newly diagnosed GBM. The study is registered with the trial registration number NCT01507506, with the registration date being December 20, 2011.
Epidemiology and Prognosis
Glioblastoma (GBM) is a highly aggressive and the most common form of primary brain tumor in adults. Epidemiologically, glioblastoma accounts for about 48% of all primary malignant brain tumors. The incidence rate of GBM is approximately 3.21 per 100,000 people annually in the United States. This cancer is more prevalent in older adults, with the median age at diagnosis being around 64 years, and it is slightly more common in men than in women.
The prognosis for patients with glioblastoma is generally poor, despite advances in neurosurgery, radiotherapy, and chemotherapy. The median overall survival (OS) for patients with newly diagnosed GBM treated with standard therapy, which includes surgical resection when feasible, followed by radiotherapy with concomitant and adjuvant temozolomide, is typically around 14.6 months. The 2-year survival rate is approximately 26.5%, and the 5-year survival rate is less than 10%.
Several factors influence the prognosis of GBM patients. Age is a significant prognostic factor, with younger patients generally having a better outcome. The extent of surgical resection also plays a critical role; more extensive resection is associated with improved survival. The presence of certain molecular markers, such as O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation, is associated with a better response to temozolomide and improved survival. Patients with MGMT promoter methylation have a median OS of about 21.7 months compared to 12.7 months for those without this genetic alteration.
It's important to note that these figures can vary based on the study and the population being examined, and ongoing research continues to seek improvements in the treatment and prognosis of GBM.
Standard Treatment
The standard treatment for newly diagnosed glioblastoma (GBM) typically involves a multimodal approach that includes maximal safe surgical resection, radiotherapy, and chemotherapy.
Surgical Resection: The initial step in treating GBM is maximal safe surgical resection. The goal of the surgery is to remove as much of the tumor as possible without compromising neurological function. Complete resection is often challenging due to the infiltrative nature of GBM and its location in the brain.
Radiotherapy: Post-surgery, patients usually undergo radiotherapy. This involves localized radiation to the brain to target any remaining tumor cells. The standard dose is 60 Gray (Gy) administered over a period of about 6 weeks. Radiotherapy is a critical component of the treatment regimen as it can significantly prolong survival and improve quality of life.
Chemotherapy: Alongside radiotherapy, patients are typically treated with the oral chemotherapy drug temozolomide. Temozolomide is given daily during radiotherapy and then in cycles for six months after radiotherapy. This drug works by damaging the DNA of cancer cells, which interferes with their ability to replicate and grow.
This multimodal approach has been the standard of care since the early 2000s, following studies that demonstrated a significant survival benefit with the addition of temozolomide to radiotherapy.
The study in question aimed to add to this standard treatment by investigating whether dose escalation of radiotherapy guided by magnetic resonance spectroscopic imaging (MRSI) could improve outcomes in patients with newly diagnosed GBM. The rationale behind this approach was that MRSI, a non-invasive imaging technique, might be able to identify areas of the brain with higher metabolic activity indicative of aggressive tumor growth. By escalating the dose of radiation to these areas (up to 72 Gy), the study hypothesized that it might be possible to more effectively target the tumor, potentially improving overall survival and progression-free survival in these patients.
This approach sought to personalize and intensify treatment by focusing on areas at high risk for tumor recurrence, which could potentially lead to better outcomes compared to the uniform radiation dose used in standard treatment. The study's findings were significant in evaluating the efficacy and safety of this innovative approach in the treatment of GBM.
Clinical Implications
The findings of the "Randomized phase III trial of metabolic imaging-guided dose escalation of radio-chemotherapy in patients with newly diagnosed glioblastoma (SPECTRO GLIO trial)" have several clinical implications and potential impacts:
Efficacy of Dose Escalation: The trial showed that MRSI-guided dose escalation to 72 Gy, in addition to standard therapy, did not improve overall survival in newly diagnosed GBM patients. This suggests that simply escalating the dose of radiotherapy, even when guided by advanced imaging techniques like MRSI, may not provide additional benefit over the standard dose for all patients.
Safety and Tolerability: Importantly, the trial found that the higher dose of radiation was well tolerated, with no significant increase in toxicity compared to the standard dose. This is a crucial aspect because it implies that higher doses of radiation can be safely administered in GBM, which could be relevant for future trials exploring other dose-intensive therapies.
Refinement of Treatment Strategies: The trial’s results contribute to the ongoing efforts to refine and personalize treatment strategies for GBM. While dose escalation in this format was not effective, the methodology and insights gained could inform future studies, perhaps focusing on more targeted radiation techniques or combining dose escalation with other novel therapies.
Implications for MRSI in GBM Management: The trial underscores the limitations of MRSI in guiding radiotherapy dose escalation in GBM. While MRSI is a promising tool for identifying metabolic abnormalities, its role in improving clinical outcomes through tailored radiotherapy needs further exploration.
Future Research Directions: The results indicate a need for continued research into more effective treatment strategies for GBM. This might include exploring different radiotherapy techniques, combining radiotherapy with novel systemic therapies, or identifying specific patient subgroups who might benefit from dose escalation.
Clinical Impact Potential: The trial’s findings contribute to the broader understanding of GBM treatment but also highlight the challenges in improving outcomes for this aggressive cancer. The lack of survival benefit with dose escalation prompts clinicians and researchers to continue seeking innovative treatment approaches. The trial reinforces the necessity of rigorous clinical testing of new treatments or modifications of existing treatments before they are adopted into standard clinical practice.
In summary, while the trial did not demonstrate an improvement in survival with MRSI-guided dose escalation, it adds valuable knowledge to the field of neuro-oncology and underscores the need for ongoing research to improve the prognosis for patients with glioblastoma.
Reference
Laprie A, Noel G, Chaltiel L, Truc G, Sunyach MP, Charissoux M, Magne N, Auberdiac P, Biau J, Ken S, Tensaouti F, Khalifa J, Sidibe I, Roux FE, Vieillevigne L, Catalaa I, Boetto S, Uro-Coste E, Supiot S, Bernier V, Filleron T, Mounier M, Poublanc M, Olivier P, Delord JP, Cohen-Jonathan-Moyal E. Randomized phase III trial of metabolic imaging-guided dose escalation of radio-chemotherapy in patients with newly diagnosed glioblastoma (SPECTRO GLIO trial). Neuro Oncol. 2024 Jan 5;26(1):153-163. doi: 10.1093/neuonc/noad119. PMID: 37417948; PMCID: PMC10768994.