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Málaga, España (Spain)
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Is glioblastoma curable?

17/February/2020

Glioblastoma multiforme or glioma grade 4 or IV, is the primary brain tumor with one of the lowest survivals in adults. It accounts for 15% of brain tumors.​

Current standard treatment consists of the greatest possible surgical resection of the tumor without leaving sequelae. Then, after 4 to 5 weeks after surgery, radiation therapy is given along with concomitant chemotherapy (with temozolomide), and then 6 cycles of adjuvant temozolomide. Despite this treatment, the average survival after initial diagnosis is about 13-15 months, and a 2-year survival rate of 27%. ​Know all types and current treatments.

In some studies, it has been recommended to start temozolomide in the first 10 days after surgery and even start before surgery with bevacizumab. In some recent clinical trials, they are injecting intratumorally modified viruses. Immunotherapy is prolonging survival by about 4 months and also the natural glioblastoma cure with certain products such as honey are promising. ​

The objectives of surgical treatment are the greatest possible surgical resection without leaving neurological sequelae, together with the collection of tumor tissue sample in order to make the pathological diagnosis and thus be able to better adjust the treatment according to the genetic and molecular variants. 

When more than 95% of the tumor mass is removed, survival improves significantly. Some authors also claim that removing 75% of tumor mass in addition to chemotherapy and radiation therapy also improve survival. ​

The use of 5-ALA, a fluorescent substance that accumulates within malignant glial cells and allows them to be seen red during surgery greatly increases the removal of malignant tissue during surgery (66% versus 34%). Its use in brain areas near language or motor areas requires intraoperative mapping. ​

We are currently conducting a combination treatment study targeting glioblastoma cancer stem cells by modulating mTOR, MGMT, VEGF, STAT3, AKT, Wnt and P53.

 

Standard treatment by type and age

 

1. Patients ≤ 70 years with methylation of MGMT

Temozolomide in combination with radiation therapy. As an alternative treatment temozolomide and lomustine may be combined with radiation therapy, although data supporting improved efficacy are inconclusive and toxicity may be higher. This combination of lomustine and temozolomide could improve survival compared to standard temozolomide in younger selected patients and in form with glioblastoma methylated MGMT.​

 

2. Patients ≤ 70 years without methylation of MGMT 

Outside of a clinical trial, temozolomide may be used in conjunction with radiation in most patients without MGMT methylation, based on the results of the EORTC/NCIC trial. Patients with non-methylated tumors have a worse survival and get less benefits with temozolomide compared to patients with methylated tumors. The addition of temozolomide to radiation therapy was associated with a small difference in survival that was not statistically significant (13 versus 12 months). ​

3. Patients ≤ 70 years in which the status of methylation of MGMT is not known

When the status of MGMT is not known at the time of postoperative decision-making and the patient is a candidate for standard therapy (i.e. age 70 years, good functional status), the use of temozolomide in combination with radiation therapy is recommended. 35% of patients are methylated and tolerance to temozolomide is good at justifying treatment. ​

4. Older adults with poor functional condition 

Temozolomide in combination with external radiation therapy (40 Gy in 15 fractions) is used. Single-modality therapy (i.e. single radiation or temozolomide alone) is usually best for older or poorly functional patients. ​

Tumor Treating Fields (TTFields, Optune)

Data from the Phase 3 (EF-14) trial were reported in ASCO 2015, showing that the addition of TTFields to temozolomide produced clinically significant survival benefits compared to the current standard of care in patients with glioblastoma just Diagnosed. Following the EF-14 trial, a panel of experts concluded that TTFields plus temozolomide represents the first major advance in the field of GBM therapy in about a decade, and should be considered for patients with newly diagnosed glioblastoma who do not have contraindications. ​

Repurposing drugs and antioxidants

There are 2 types of alternative or complementary therapies that are currently being intensively researched in controlled clinical trials:

- Repurposing drugs

- Natural substances

Both are allied against glioblastoma and an appropriate combination based on different mechanisms of action against glioblastoma are the complement that can increase effectiveness against cancer cells including stem cells. ​

Repurposing drugs combination strategy.

 

Vaccine therapies

DCVax-L (or DCVax-Brain) is a vaccine made with autologous dendritic cells with tumor-derived tumor evidence, the vaccine is injected intradermally from where the immune response to the tumor is activated. Phase 1 and 2 trials demonstrated their safety and evidence of T-cell infiltration in several of the recurrent tumors. He is currently in a phase 3 clinical trial.

Rindopepimut (CDX-110) is a vaccine consisting of an eGFRvIII peptide conjugated with hemocyanine. While initial phase 1 and 2 studies (VICTORI, ACTIVATE, ACTII, ACTIII) demonstrated the safety of the vaccine but a large randomized phase 3 trial called ACT IV, unfortunately it showed no improvement in the survival of the treated groups. ​

NeoVax (Personalized NeoAntigen Vaccine)

Terapias con celulas (CAR-T)

The latest and one of the bests technologies with cell therapy by genetic modification of T immune cells to improve antitumor responsiveness. T cells modified by chimeric antigen receptors (CAR-T cells) have shown positive responses in patients with refractory leukemia to conventional usual treatment. This technology has been used in phase 1 trials of glioblastoma patients. IL13R-2-specific CAR T cells administered intracerebrally to patients with recurrent glioblastomas are safe and appear to have an effect against this cancer. HER2-specific CAR T cells have been repeatedly given to patients with glioblastoma without significant side effects. More studies will be needed to determine whether cell therapies can work in gliomas patients.

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