a decrease in headache or drowsiness. surgery surgery is the first stage of treatment of glioblastoma. an average gbm tumor contains 1011 cells, which is on average reduced to 109 cells after surgery (a reduction of 99%). benefits of surgery include resection for a pathological diagnosis, alleviation of symptoms related to mass effect, and potentially removing disease before secondary resistance to radiotherapy and chemotherapy occurs. the greater the extent of tumor removal, the better. in retrospective analyses, removal of 98% or more of the tumor has been associated with a significantly longer healthier time than if less than 98% of the tumor is removed. the chances of near-complete initial removal of the tumor may be increased if the surgery is guided by a fluorescent dye known as 5-aminolevulinic acid. gbm cells are widely infiltrative through the brain at diagnosis, and despite a "total resection" of all obvious tumor, most people with gbm later develop recurrent tumors either near the original site or at more distant locations within the brain. other modalities, typically radiation and chemotherapy, are used after surgery in an effort to suppress and slow recurrent disease through damaging the dna of rapidly proliferative gbm cells. radiotherapy subsequent to surgery, radiotherapy becomes the mainstay of treatment for people with glioblastoma. it is typically performed along with giving temozolomide. a pivotal clinical trial carried out in the early 1970s showed that among 303 gbm patients randomized to radiation or best medical therapy, those who received radiation had a median survival more than double those who did not. subsequent clinical research has attempted to build on the backbone of surgery followed by radiation. whole-brain radiotherapy does not improve when compared to the more precise and targeted three-dimensional conformal radiotherapy. a total radiation dose of 60–65 gy has been found to be optimal for treatment. gbm tumors are well known to contain zones of tissue exhibiting hypoxia, which are highly resistant to radiotherapy. various approaches to chemotherapy radiosensitizers have been pursued, with limited success as of 2016. as of 2010, newer research approaches included preclinical and clinical investigations into the use of an oxygen diffusion-enhancing compound such as trans sodium crocetinate as radiosensitizers, and as of 2015 a clinical trial was underway. boron neutron capture therapy has been tested as an alternative treatment for glioblastoma, but is not in common use. chemotherapy most studies show no benefit from the addition of chemotherapy. however, a large clinical trial of 575 participants randomized to standard radiation versus radiation plus temozolomide chemotherapy showed that the group receiving temozolomide survived a median of 14.6 months as opposed to 12.1 months for the group receiving radiation alone. this treatment regimen is now standard for most cases of glioblastoma where the person is not enrolled in a clinical trial. temozolomide seems to work by sensitizing the tumor cells to radiation, and appears more effective for tumors with mgmt promoter methylation. high doses of temozolomide in high-grade gliomas yield low toxicity, but the results are comparable to the standard doses. antiangiogenic therapy with medications such as bevacizumab control symptoms, but do not appear to affect overall survival in those with glioblastoma. the overall benefit of anti-angiogenic therapies as of 2019 is unclear. in elderly people with newly diagnosed glioblastoma who are reasonably fit, concurrent and adjuvant chemoradiotherapy gives the best overall survival but is associated with a greater risk of haematological adverse events than radiotherapy alone. other procedures alternating electric field therapy is an fda-approved therapy for newly diagnosed and recurrent glioblastoma. in 2015, initial results from a phase-iii randomized clinical trial of alternating electric field therapy plus temozolomide in newly diagnosed glioblastoma reported a three-month improvement in progression-free survival, and a five-month improvement in overall survival compared to temozolomide therapy alone, representing the first large trial in a decade to show a survival improvement in this setting. despite these results, the efficacy of this approach remains controversial among medical experts. however, increasing understanding of the mechanistic basis through which alternating electric field therapy exerts anti-cancer effects and results from ongoing phase-iii clinical trials in extracranial cancers may help facilitate increased clinical acceptance to treat glioblastoma in the future. a tel aviv university study showed that pharmacological and molecular inhibition of the p-selectin protein leads to reduced tumor growth and increased survival in mouse models of glioblastoma. the results of this research could open to possible therapies with drugs that inhibit this protein, such as crizanlizumab. prognosis the most common length of survival following diagnosis is 10 to 13 months (although recent research points to a median survival rate of 15 months), with fewer than 1–3% of people surviving longer than five years. in the united states between 2012 and 2016 five-year survival was 6.8%. without treatment, survival is typically 3 months. complete cures are extremely rare, but have been reported. increasing age (> 60 years) carries a worse prognostic risk. death is usually due to widespread tumor infiltration with cerebral edema and increased intracranial pressure. a good initial karnofsky performance score (kps) and mgmt methylation are associated with longer survival. a dna test can be conducted on glioblastomas to determine whether or not the promoter of the mgmt gene is methylated. patients with a methylated mgmt promoter have longer survival than those with an unmethylated mgmt promoter, due in part to increased sensitivity to temozolomide. another positive prognostic marker for glioblastoma patients is mutation of the idh1 gene, which can be tested by dna-based methods or by immunohistochemistry using an antibody against the most common mutation, namely idh1-r132h. more prognostic power can be obtained by combining the mutational status of idh1 and the methylation status of mgmt into a two-gene predictor. patients with both idh1 mutations and mgmt methylation have the longest survival, patients with an idh1 mutation or mgmt methylation an intermediate survival, and patients without either genetic event have the shortest survival. long-term benefits have also been associated with those patients who receive surgery, radiotherapy, and temozolomide chemotherapy. however, much remains unknown about why some patients survive longer with glioblastoma. age under 50 is linked to longer survival in gbm, as is 98%+ resection and use of temozolomide chemotherapy and better kpss. a recent study confirms that younger age is associated with a much better prognosis, with a small fraction of patients under 40 years of age achieving a population-based cure. cure is thought to occur when a person's risk of death returns to that of the normal population, and in gbm, this is thought to occur after 10 years. ucla neuro-oncology publishes real-time survival data for patients with this diagnosis. according to a 2003 study, gbm prognosis can be divided into three subgroups dependent on kps, the age of the patient, and treatment. recursive partitioning analysis(rpa) classdefinitionhistorical median survival timehistorical 1-year survivalhistorical 3-year survivalhistorical 5-year survival iiiage < 50, kps ≥ 9017.1 months70%20%14% ivage < 50, kps < 9011.2 months46%7%4% age ≥ 50, kps ≥ 70, surgical removal with good neurologic function v + viage ≥ 50, kps ≥ 70, surgical removal with poor neurologic function7.5 months28%1%0% age ≥ 50, kps ≥ 70, no surgical removal age ≥ 50, kps < 70 epidemiology about three per 100,000 people develop the disease a year, although regional frequency may be much higher. the frequency in england doubled between 1995 and 2015. it is the second-most common central nervous system cancer after meningioma. it occurs more commonly in males than females. although the average age at diagnosis is 64, in 2014, the broad category of brain cancers was second only to leukemia in people in the united states under 20 years of age. history the term glioblastoma multiforme was introduced in 1926 by percival bailey and harvey cushing, based on the idea that the tumor originates from primitive precursors of glial cells (glioblasts), and the highly variable appearance due to the presence of necrosis, hemorrhage, and cysts (multiform). research gene therapy gene therapy has been explored as a method to treat glioblastoma, and while animal models and early-phase clinical trials have been successful, as of 2017, all gene-therapy drugs that had been tested in phase-iii clinical trials for glioblastoma had failed. scientists have developed the core–shell nanostructured lplnp-ppt (long persistent luminescence nanoparticles. ppt refers to polyetherimide, peg and trans-activator of transcription, and trail is the human tumor necrosis factor-related apoptosis-induced ligand) for effective gene delivery and tracking, with positive results. this is a trail ligand that has been encoded to induce apoptosis of cancer cells, more specifically glioblastomas. although this study was still in clinical trials in 2017, it has shown diagnostic and therapeutic functionalities, and will open great interest for clinical applications in stem-cell-based therapy. oncolytic virotherapy oncolytic virotherapy is an emerging novel treatment that is under investigation both at preclinical and clinical stages. several viruses including herpes simplex virus, adenovirus, poliovirus, and reovirus are currently being tested in phases i and ii of clinical trials for glioblastoma therapy and have shown to improve overall survival. intranasal drug delivery direct nose-to-brain drug delivery is being explored as a means to achieve higher, and hopefully more effective, drug concentrations in the brain. a clinical phase-i/ii study with glioblastoma patients in brazil investigated the natural compound perillyl alcohol for intranasal delivery as an aerosol. the results were encouraging and, as of 2016, a similar trial has been initiated in the united states. cannabinoids the efficacy of cannabinoids (cannabis derivatives) is known in oncology (through capsules of tetrahydrocannabinol (thc) or the synthetic analogue nabilone), on the one hand to combat nausea and vomiting induced by chemotherapy, on the other to stimulate appetite and lessen the sense of anguish or the actual pain. their ability to inhibit growth and angiogenesis in malignant gliomas in mouse models has been demonstrated. the results of a pilot study on the use of thc in end-stage patients with recurrent glioblastoma appeared worthy of further study. a potential avenue for future research rests on the discovery that cannabinoids are able to attack the neoplastic stem cells of glioblastoma in mouse models, with the result on the one hand of inducing their differentiation into more mature, possibly more "treatable" cells, and on the other hand to inhibit tumorigenesis.