Glioblastoma Multiforme (GBM): The Current Standard
- Glioblastoma (GBM), a grade IV glioma, presents significant challenges for treatment due to its highly invasive nature, rapid growth, and resistance to most conventional therapies.
- While new treatment approaches are continually being explored through clinical trials, the standard of care for glioblastoma has remained largely consistent since 2005. It combines maximal safe surgical resection (surgery to remove as much of the cancer as possible) followed by chemotherapy and radiation.
- The typical course after surgery is chemotherapy and radiation therapy together, followed by additional chemotherapy.
- More recently, a clinical trial found that the addition of tumor treating fields (Optune) to the chemotherapy following combined chemoradiation improved survival further with minimal increase in toxicity.
- Tumor Treating Fields, or TTF therapy, is delivered via a wearable device called Optune. It uses alternating electric fields to inhibit tumor growth.
Despite advances in neurosurgery, chemotherapy, radiation therapy, and supportive care, glioblastoma remains a highly fatal disease, with median survival rates of approximately 20 months and a five-year survival rate of approximately 10%.
Read MoreHere, we will go into each aspect of treatment in further detail and explain the basics, practical considerations, expected outcomes, toxicities, and limitations related to each step of treatment.
Maximal Safe Surgical Resection
Following appropriate workup — which consists of a detailed medical history, neurologic exam, lab work assessing blood counts and metabolic levels, and an MRI of the brain — a decision can be made regarding potential surgery. If glioblastoma is suspected based on presentation and MRI imaging, a tissue biopsy is necessary to confirm the presence of glioblastoma and determine the appropriate treatment.
Surgery is the first line of treatment for patients diagnosed with glioblastoma. “The surgical goals is safe maximal resection, so what that entails is really studying the preoperative imaging” says Dr. Shankar.
With maximal safe resection, the goal is to remove as much of the tumor as possible while minimizing damage to surrounding healthy brain tissue. Several tools are used to make this possible.
When Surgery is Not Possible
Sometimes, surgery is not possible or would be of limited use as only a small portion of the tumor could be removed safely. This can be due to a variety of reasons related to the glioblastoma or patient specific factors, such as the location of the tumors or medical problems that make the patient an unsafe candidate for surgery.
Glioblastomas often invade critical areas of the brain involved in functions such as movement, speech, or cognition. Surgeons must balance the goal of removing as much tumor as possible with the need to preserve these functions. Several tools are used to make these decisions.
“Sometimes, we obtain images that allow us to see tracks in the brain that’s called tractography, so that we can see how the different language centers or the motor strip function or the visual cortex is lined up and how the mass is interacting with those tracks that helps us understand exactly and predict how to plan for the surgery. Many times these surgeries are performed with our intraoperative GPS system to make sure that we know exactly where the location of the mass is relative to the scalp,” Dr. Shankar explains.
If you are not a candidate for surgery a tissue biopsy is still required to make a diagnosis of glioblastoma. This can be performed via a stereotactic biopsy where a small hole is made in the skull and small piece of tissue is obtained via a long needle that is guided with imaging. Again, an attempt at maximal safe resection is preferred when possible to achieve the best survival outcomes, but a biopsy can be considered in select cases.
After Surgery
Following a maximal safe resection, and ideally a gross total resection (where all of the tumor seen during surgery and on imaging is removed), the tissue is sent for analysis. The tissue is examined under the microscope (called histopathology) and tested for specific molecular markers and genetic mutations. These analyses tests to confirm if the tumor is a glioblastoma or a lower grade glioma. This helps to inform treatment decisions, and certain markers with glioblastoma, can inform the prognosis. For example, it is known that MGMT promoter methylated glioblastomas have better survival as compared to MGMT unmethylated tumors.
Even if a gross total resection is performed and there is no clear or minimal evidence of tumor on imaging after surgery, glioblastoma tends to infiltrate the brain in a diffuse manner, making it impossible to completely eradicate the tumor through surgery alone. Because of this, it is necessary to continue with adjuvant treatment. Adjuvant treatment is a term that describes other cancer therapies that are performed after the main treatment, being surgery.
So following surgery, what is the next step in treatment?
Radiation and Chemotherapy (Chemoradiation)
Radiation Therapy
Radiation therapy is a critical component of the standard treatment for glioblastoma and typically follows surgery. Radiation delivers targeted, high powered x-rays to the surgical site and any areas concerning for residual disease. Radiation primarily works by causing DNA damage. This DNA damage is easier for normal tissue to repair, however cancer cells have defective repair mechanisms and this DNA damage accumulates which leads to cancer cell death. The primary goal of radiation is to destroy any remaining tumor cells and delay tumor recurrence. The current standard radiation protocol for glioblastoma involves fractionated external beam radiation therapy (EBRT). This means the treatment is broken up (or fractionated) into several treatments, and the radiation is delivered by a radiation beam from outside the body.
Radiation Planning
Prior to initiation of radiation therapy, a planning scan is performed. This is also called a CT simulation scan. This is combined with a recent MRI scan performed following surgery. The two scans are used together to create a plan that adequately covers the target area (being the surgery site and potential residual disease) while reducing radiation dose to important normal organs including the brainstem and nerves that control vision.
Several advances in radiation delivery have been made in the past decades which allow doctors to treat these cancers effectively, while further reducing dose to normal tissue. This includes intensity-modulated radiation therapy (IMRT) which uses advanced computer planning software to create the ideal radiation plan using multiple complex radiation beams and angles. Radiation therapy has been shown to improve survival in patients with glioblastoma and is an important part of treatment after surgery.
Radiation Regimen
The standard course of radiation therapy is delivered over a period of six weeks, with patients receiving radiation once daily, five days a week.
A total dose of 60 Gy (gray units, a measure of radiation dose) is typically administered in 2 Gy fractions per day. This fractionated approach helps to minimize damage to healthy brain tissue, allowing time for repair in normal tissue, while delivering a sufficient dose to the tumor, which is more sensitive to the effects of radiation.
“In older or more frail patients that are felt to be unable to tolerate the complete course of radiation and chemotherapy, they can undergo radiation in a shorter treatment schedule, typically for three weeks,” shares Dr. James Taylor, radiation oncologist with North Georgia Physicians Group.
Radiation therapy is targeted specifically to the tumor bed and areas concerning for residual disease. A small margin around these areas is treated as well, as glioblastoma tends to return locally around the surgical site.
Radiation Side Effects
Radiation treatment is typically well-tolerated. Each treatment itself only last a few minutes. Because X-rays are being delivered, much like a CT scan or Chest X-ray, you will not feel anything during the treatment itself. For the first several days to weeks of radiation side effects will be minimal.
As the dose adds up after the first few weeks of radiation, you are more likely to experience side effects related to the treatment. The side effects are often local, meaning they happen where the radiation is being delivered.
Common side effects that can be experience include:
- Fatigue
- Headache
- Skin irritation over the scalp
- Hair loss
Most symptoms if experienced, typically resolve in the weeks following completion of radiation.
For standard-of-care treatment for glioblastoma, radiation is delivered at the same time as chemotherapy.
Chemotherapy: Temozolomide
The addition of chemotherapy during radiation treatment has been demonstrated to improve survival and slow progression of disease. The current standard chemotherapy agent used for treatment of glioblastoma is temozolomide (TMZ). Temozolomide is a pill taken by mouth. It works by stopping production of DNA, which is needed in cancer cells to continue to grow and divide.
Chemoradiation Protocol
When Temozolomide is given at the same time as radiation, it is called concurrent treatment or chemoradiation. During this phase, patients receive a daily dose of Temozolomide (75 mg/m²) throughout the six weeks of radiation therapy which is taken even on days radiation is not being delivered.
The Temozolomide dose delivered during radiation is a lighter dose and fairly well tolerated.
Some side effects that can arise include:
- A drop in blood counts (which can increase risk of bleeding and infection)
- Nausea
- Constipation
- Skin irritation
- Allergic reactions
- Liver injury
- Seizures
It is important to get regular labs and follow closely with your care team during chemoradiation in order to manage side effects or symptoms should they occur.
Chemotherapy and Tumor Treating Fields (Optune)
Dr. Taylor tells SurvivorNet, “Following the completion of chemoradiation, they will typically have a month of treatment break after which new MRI scans will be obtained to assess treatment response. Following the month of a break, you will then resume treatment with a combination of temozolomide chemotherapy and tumor treating fields (Optune).”
During this phase, Temozolomide is administered in higher doses (150-200 mg/m²) for five days every 28 days, typically for six to twelve cycles. You will continue to be followed by your medical oncologist with regular visits and lab work to follow your blood counts. During this time you will also be recommended to undergo treatment with tumor treating fields (optune). This part of treatment will start at the same time as the high-dose chemotherapy and the Optune will be worn as a head-wrap continuously.
Tumor Treating Fields (Optune)
Tumor Treating Fields (Optune) represent a relatively new addition to the standard treatment for glioblastoma. TTF therapy, delivered via a wearable device called Optune, uses alternating electric fields to disrupt cell division, thereby inhibiting tumor growth.
The Optune device uses adhesive pads with electrodes that are applied directly to the skin. These are called transducer arrays and typically four of them are applied to the scalp.
In order to be applied, you need to shave your head prior to the using Optune. The Optune pads are worn continuously throughout the day for a long as possible, with minimal interruptions or breaks. For Optune to be maximally effective, studies have shown the pads need to be worn and activated for at least 18 hours each day, seven days a week.
The Optune device can be used for up to 24 months or until the disease progresses twice.
The pivotal trial for tumor treating fields demonstrated that adding to maintenance Temozolomide therapy extended both progression-free survival and overall survival compared to Temozolomide alone.
The use of Optune does not increase the rate of side effects from chemotherapy. In regards to Optune specifically, it is common to experience mild to moderate skin irritation on the scalp when using the device, including itching and rash. It is extremely uncommon to experience a severe skin reaction.
Supportive and Palliative Care
In addition to the active treatment of surgery, chemoradiation, and chemotherapy with tumor treating fields, supportive care is essential for managing the symptoms and side effects associated with glioblastoma and its treatments.
This can include:
- Corticosteroids: Used to reduce brain swelling (edema) and alleviate symptoms such as headaches or neurological deficits.
- Antiepileptic drugs: Seizures are common in glioblastoma patients, and antiepileptic medications are used to prevent or control them.
- Physical, occupational, and speech therapy: To help patients regain function or adapt to neurological impairments.
- Palliative care: Focuses on improving quality of life and managing symptoms such as pain, fatigue, and depression. Palliative care is integrated into the treatment plan from the time of diagnosis and becomes more prominent as the disease progresses.
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