Brain Tumor - Glioblastoma
Determining the Treatment Approach
Glioblastoma is notoriously difficult to treat effectively, partly because every patient’s tumor has different molecular and cellular characteristics. These characteristics can vary even within the same tumor. Research continues to examine ways to personalize glioblastoma treatment, with the hope of improving outcomes by creating a treatment plan specific for each tumor’s unique characteristics. Most treatment planning is still based largely on more general characteristics, such as patient age, functional status (KPS Index score), and more recently, MGMT methylation status (Thon 2013; Weller 2012; Colombo 2015). Initial surgery is the mainstay of treatment for most people with glioblastoma, followed by radiotherapy and/or chemotherapy (NCCN 2016; Stupp 2005).
Surgery and Local Chemotherapy
Surgery is an essential part of glioblastoma treatment (NCCN 2016). Surgical removal (resection) of a glioblastoma tumor can relieve symptoms, extend life, and decrease the need for corticosteroids to reduce brain swelling. The amount of tumor that can be removed through surgery depends on its location, as well as the patient's age and health status. Ideally, surgeons aim for what is referred to as a maximum safe resection, which will remove most or all of the tumor (Roder 2014; Kuhnt 2011; Li, Suki 2016). In some cases, glioblastoma tumor cells spread in different directions so that the tumor may not be a simple solid mass, making total resection impossible (Davis 2016). Within three days after surgery, and preferably within the first 24 hours, MRI scans are necessary to determine how much of the tumor was removed. For those unable to undergo MRI, CT scans with and without contrast can be performed (Pirzkall 2009; Sanghvi 2015; Kumar 2013).
During surgery, some patients may be treated with a form of chemotherapy delivered locally to the tumor site (NCCN 2016; Zhang, Dai 2014). A drug called carmustine is contained in a wafer, and up to eight wafers may be placed into the space where the tumor was. Placing the wafers directly into the brain helps the drug target any remaining tumor cells without damaging healthy cells in other parts of the body (NCI 2018). The wafers dissolve over time after surgery (Mangraviti 2015). Although this form of chemotherapy may extend the life of the patient, it can cause complications (Lara-Velazquez 2017; Bock 2010). For example, carmustine may interact with some other drugs and increase their toxicity (NCCN 2016). Also, some patients may experience swelling in the brain, seizures, healing problems, or local infections (Sabel 2008; Giese 2010).
Unlike carmustine wafers, some other chemotherapeutic drugs are delivered to the whole body through the bloodstream. This is called “systemic” therapy and is accomplished by using pills taken orally or liquids injected into a vein (NCCN 2016). Some patients will only receive one drug, usually the alkylating agent temozolomide. Temozolomide damages the DNA (Erasimus 2016). Cancer cells are growing and dividing rapidly and are more sensitive to DNA damage (O'Connor 2015; Baskar 2014). Tumors with MGMT methylation may be more sensitive to alkylating agents (Fernandes 2017; Davis 2016). For some patients, several drugs are used to fight the cancer in multiple ways (NCCN 2016).
Because systemic chemotherapy can be hard on a patient’s body, the treatments are normally spaced out in a series of cycles, typically two to four weeks each (NCCN 2016). Side effects of systemic chemotherapy will depend on the drug, dose, and individual patient. Because chemotherapy drugs typically target rapidly dividing cells, healthy cells that also divide rapidly, such as those in the digestive tract, blood, and hair follicles, may also be affected by the drug. Common side effects of systemic chemotherapy include low blood cell counts, loss of appetite, nausea, fatigue, vomiting, diarrhea, hair loss, and mouth sores (Hershman 2008; Rahnama 2015; Stein 2010; Mustian 2011).
More general information about chemotherapy, including strategies to reduce chemotherapy side effects, is available in the Chemotherapy protocol.
Temozolomide has improved glioblastoma treatment outcomes over the past two decades. However, not all cancers are sensitive to temozolomide, and even those that start out sensitive typically develop ways to overcome the drug (Ramirez 2013).
Finding ways to overcome or prevent temozolomide resistance is a critical area of research. Many of the compounds discussed in the Integrative Interventions section, such as melatonin, vitamin D, and selenium, are being tested in laboratory studies to see if they can make glioblastoma cells more sensitive to temozolomide.
Repurposed drugs like metformin and cimetidine are also being analyzed in the same way. In one recent study, researchers selected 21 drugs promising or already known to work against various kinds of cancer (Teng 2017). They tested whether the drugs would make glioblastoma cells more sensitive to temozolomide. One drug called hydroxyurea, a treatment for sickle cell disease and some types of cancer, was clearly the standout. Hydroxyurea sensitized all types of glioblastoma cells and tumors in mice to temozolomide, regardless of the MGMT methylation status.
Another drug called trans sodium crocetinate (TSC) is designed to make tumors more sensitive to temozolomide and radiation, possibly by increasing the oxygen content (Sheehan 2010). In a phase II clinical trial, 36% of patients treated with TSC in addition to temozolomide and radiation were still alive after two years (Gainer 2017). Preparation for a phase III clinical trial is currently underway to compare TSC-treated patients to a control group.
Tumors rely on the growth of new blood vessels or angiogenesis to provide nutrition to each cell. A monoclonal antibody called bevacizumab (Avastin) prevents angiogenesis by blocking the vascular endothelial growth factor (VEGF) signaling pathway (NCCN 2016). VEGF signaling is often increased in glioblastoma tumors and contributes to tumor growth. Bevacizumab was approved in 2009 for treatment of recurrent glioblastoma (Davis 2016). A review study found that bevacizumab could improve patients’ median survival by four months for recurrent glioblastoma, as compared to those not taking the drug (Diaz 2017). Side effects can occur with bevacizumab, and patients must be monitored for excessive bleeding or blood clots (Diaz 2017; Davis 2016).
Some glioblastoma tumors cannot be surgically removed. Patients in these situations are treated with radiation therapy (NCCN 2016; Tamura 2017). Additionally, radiation therapy can be used to treat patients after surgery, with the goal of killing any cancer cells that may have been left behind (NCI 2018). This form of therapy uses high-energy, highly focused rays to damage and destroy cancer cells. Modern radiation therapy uses techniques designed to minimize damage to nearby healthy tissues (Narayana 2006; Gzell 2017). Most patients with glioblastoma receiving radiotherapy will be treated with a method called external beam radiation therapy (EBRT), in which radiation from a large machine passes through the skin and bone and into the brain tissue (NCCN 2016). The treatment machinery is adjusted to deliver radiation as carefully as possible to the tumor area, limiting exposure to healthy tissue.
For more complete information on radiation therapy techniques and side effects, see the Radiation Therapy protocol.
Tumor-treating fields, or alternating electric field therapy, is a technique that utilizes low-intensity electromagnetic energy to stop cells from dividing (Fernandes 2017; Hottinger 2016). The treatment uses patches taped to the patient's head and a portable battery-powered device (NCCN 2016; Saria 2016). The patches must be worn at least 18 hours per day. This technique is relatively safe, and mild-to-moderate local skin irritation is the most commonly reported side effect (Fernandes 2017).
In a 2017 randomized controlled trial, 695 people with glioblastoma were treated with tumor-treating fields along with temozolomide or temozolomide alone. The median time to survival without disease progression was 6.7 months in the tumor-treating field group, as compared with 4 months in the temozolomide-only group (Stupp 2017). The FDA initially approved tumor-treating fields for patients with recurrent glioblastoma in 2011, and expanded that approval in 2015 to include patients newly diagnosed with glioblastoma (Fernandes 2017).
Follow-Up and Continuing Care
MRI scans should be conducted two to six weeks after the end of radiation therapy (NCCN 2016). Additional scans should be performed every two to four months to check for any new brain tumors as early as possible. Those who cannot undergo MRI (such as those with certain types of pacemakers or defibrillators) can receive CT scans with and without contrast.
Most glioblastomas grow back (Stupp 2005; Davis 2016). MR spectroscopy, MR perfusion, or another scanning technique called positron emission tomography (PET) may help confirm recurrences (NCCN 2016). Treatment options for recurrences are similar to options for newly diagnosed disease. Surgery with or without carmustine wafers may be an option for recurrent tumors that are not widespread. In some cases, the goal of surgery is to alleviate symptoms (Davis 2016). For recurrences, systemic chemotherapy, radiation therapy, bevacizumab, and tumor-treating field therapy may be used (Fernandes 2017).
Supportive (or palliative) care is not intended to treat the cancer, but may enhance the patient’s quality of life and alleviate symptoms (Davis 2016; NCCN 2016). Examples of supportive interventions include the use of glucocorticoids, a type of steroid, to reduce swelling in the brain. Additionally, supportive care may involve treating a patient's depression or fatigue, decreasing delirium or agitation, improving cognition, and controlling seizures (Seekatz 2017; Koekkoek 2016). Supportive care may be the only option for patients with advanced or recurrent glioblastoma.