Glioblastoma (GBM) is the most aggressive and common malignant primary brain tumor in adults, historically associated with a challenging prognosis. Diagnosis has fundamentally transformed, moving from relying solely on microscopic appearance to including precise molecular classification. The contemporary standard, established by the World Health Organization (WHO), now integrates specific genetic markers to define distinct disease entities. This shift allows for a more accurate understanding of a tumor’s biology and its likely response to treatment. Glioblastoma is now specifically defined by the absence of a particular genetic change, creating a more homogeneous group for diagnosis and therapeutic planning.
Defining IDH Wild Type Glioblastoma
The designation “IDH wild type” is central to the modern diagnosis of this tumor type, referring to the status of the Isocitrate Dehydrogenase (IDH) gene. IDH is an enzyme fundamental to cellular metabolism. The term “wild type” signifies that the IDH1 and IDH2 genes are normal and have not acquired a mutation.
In contrast, an IDH-mutant tumor carries a specific gene change, which alters the enzyme’s function and is associated with a different, often less aggressive, disease course. Under the 2021 WHO Classification of CNS Tumours, only tumors lacking the IDH mutation are classified as Glioblastoma, IDH-wild type, categorized as WHO CNS Grade 4. This molecular definition ensures glioblastoma is a biologically distinct entity, representing approximately 90% of all glioblastoma cases. These tumors typically arise de novo, meaning they develop rapidly without evidence of a pre-existing, lower-grade glioma.
Biological Characteristics and Clinical Prognosis
IDH-wild type glioblastoma is characterized by rapid growth and a highly infiltrative nature, allowing tumor cells to spread throughout the surrounding brain tissue. This aggression stems from specific genetic alterations that drive unchecked cell proliferation and resistance to cell death.
Common molecular features include amplification of the Epidermal Growth Factor Receptor (EGFR) gene, which occurs in 40% to 50% of cases and promotes continuous cell signaling for growth. Another frequent alteration is the mutation of the Telomerase Reverse Transcriptase (TERT) promoter, found in 70% to 80% of tumors, which enables cells to achieve immortality. Other hallmark genetic signatures include the loss of the tumor suppressor gene PTEN or the combined gain of chromosome 7 and loss of chromosome 10. These molecular defects result in a poor clinical prognosis. The median overall survival for a newly diagnosed patient is approximately 14 to 15 months following the standard therapeutic protocol.
Standard Treatment Protocols
The established therapeutic approach for newly diagnosed IDH-wild type glioblastoma is a multi-modal strategy known as the Stupp Protocol. Treatment begins with maximal safe surgical resection, aiming to remove as much visible tumor mass as possible. Because of the tumor’s infiltrative nature, complete removal is challenging, but surgery reduces tumor burden and obtains tissue for definitive diagnosis and molecular profiling.
Following recovery, the patient begins the second phase: concurrent radiation therapy and chemotherapy. Radiation is delivered to the tumor site, typically totaling 60 Gray over six weeks, targeting local disease control. Concurrently, the oral chemotherapy agent Temozolomide (TMZ) is administered daily. TMZ is an alkylating agent that damages tumor cell DNA and is effective because it can cross the blood-brain barrier.
The final phase involves adjuvant chemotherapy, starting after a short break. This phase consists of six cycles of high-dose Temozolomide, taken for five days during each 28-day cycle. This systematic combination of surgery, radiation, and chemotherapy is the standard of care and provides the longest documented survival benefit for patients with this aggressive diagnosis.
Targeted and Emerging Therapeutic Approaches
Beyond the standard Stupp Protocol, researchers are investigating new therapeutic strategies that exploit the unique biological vulnerabilities of IDH-wild type glioblastoma. Targeted therapies aim to directly block signaling pathways driven by common genetic alterations, such as frequent EGFR amplification. While historically challenging due to the blood-brain barrier and tumor heterogeneity, developing new inhibitors that better penetrate the brain is a major focus.
Immunotherapy is another direction, attempting to harness the patient’s own immune system to fight the cancer. This includes checkpoint inhibitors, which release the brakes on immune cells, and therapeutic vaccines, designed to train the immune system to recognize and attack tumor-specific antigens. Furthermore, Tumor Treating Fields (TTFields), a device-based therapy, has been incorporated into some regimens. TTFields uses alternating electrical fields to disrupt cell division, offering a non-chemotherapeutic option often used in combination with standard treatments or at recurrence.