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%). It is used to take a section for a pathological diagnosis, to remove some of the symptoms of a large mass pressing against the brain, to remove disease before secondary resistance to radiotherapy and chemotherapy, and to prolong survival.

The greater the extent of tumor removal, the better. 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 can be greatly 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 so 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 "satellite lesions" within the brain. Other modalities, including radiation, are used after surgery in an effort to suppress and slow recurrent disease.

In other cancers where radiation can prolong survival or even cure tumors, the addition of chemotherapy to radiation improves survival over radiation treatment alone. Examples include cervical cancer, throat cancer and others. Because of this, several large clinical trials took place in which it was hoped survival of GBM patients might be improved with the addition of chemotherapy to radiation. Most of these studies showed 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 regime is now standard for most cases of glioblastoma where the patient is not enrolled in a clinical trial. Temozolomide seems to work by sensitizing the tumor cells to radiation.

The U.S. Food and Drug Administration approved Avastin (bevacizumab) to treat patients with glioblastoma at progression after standard therapy based on the results of 2 studies that showed Avastin reduced tumor size in some glioblastoma patients. In the first study, 28% of glioblastoma patients had tumor shrinkage, 38% survived for at least one year, and 43% survived for at least 6 months without their disease progressing.[38] Unlike the case for colon cancer, lung cancer and other cancers where bevacizumab acts by potentiating chemotherapy, the studies leading to approval showed that in GBM, the addition of chemotherapy to bevacizumab did not improve on results from bevacizumab alone. Bevacizumab reduces brain edema and consequent symptoms, and it may be that the benefit from this drug is due to its action against edema rather than any action against the tumor itself. Some patients with brain edema do not actually have any active tumor remaining, but rather develop the edema as a late effect of prior radiation treatment. This type of edema is difficult to distinguish from that due to tumor, and both may coexist. Both respond to bevacizumab.

Relapse of glioblastoma is attributed to the recurrence and persistance of tumor stem cells. In a small trial, a tumor B-cell hybridoma vaccine against tumor stem cells elicited a specific tumor immune reaction thus enhancing immune response to the disease. Larger trials, including tests of different EGFR signaling patterns and their relationship to tumor stem cells being conducted by John A. Boockvar's lab at Weill Cornell Medical College, are in progress to further assess this approach to treating glioblastoma.

The use of alternating electrical fields to interfere with the division of malignant cells is a new approach to cancer treatment. As opposed to the treatment modalities of surgery, radiation and chemotherapy, which are all used to treat other types of cancer, alternating electrical fields is being explored for the first time in the treatment of glioblastoma. The underlying theory is that in an electrical field of given wavelength, cells attempting to divide will be destroyed. This approach is optimal for brain tumors in that normal brain cells do not divide, but cancer cells within the brain do. GBM patients treated with alternating electrical fields wear electrodes on the scalp attached to the portable Novo-TTF device. The recently released preliminary abstract of a large clinical trial of patients with relapsed GBM showed that treatment with the Novo-TTF device was no better than best supportive care in prolonging survival. A currently open clinical trial for people with newly diagnosed GBM is exploring whether the addition of the Novo-TTF device to standard radiation and temozolomide treatment improves survival over standard treatment alone.