Medical Management of Brain Metastases

Brain metastases, a common yet serious complication of systemic cancers, represent a significant challenge in oncology. Brain metastases occur when cancer cells from a primary tumor somewhere else in the body spread to the brain and disrupt the brain’s normal function.

The management of brain metastases therefore requires a multidisciplinary approach. To this end, recent advances in medical therapies have provided new hope for patients facing this complex condition.

Brain metastases are more common than primary brain tumors and affect up to 20-40% of all cancer patients. Most brain metastases originate from lung cancer, breast cancer, melanoma, and renal cell carcinoma (a type of cancer in the kidneys).

In metastasis to the brain, cancer cells invade blood vessels, cross the blood-brain barrier, and establish secondary tumors within the brain parenchyma, which is the tissue we commonly think of as “the brain.”

The cornerstone of treatment for brain metastases entails surgery and radiation therapy. Surgical resection is considered for solitary or large lesions causing mass effect, a complication where the lesion displaces or pushes on other parts of the brain. Whole-brain radiation therapy (WBRT) is a standard treatment for multiple brain metastases.

Stereotactic radiosurgery (SRS), meanwhile, delivers precise, high-dose radiation to specific lesions, sparing surrounding healthy tissue. Systemic chemotherapy is another option, but it has limited efficacy due to the blood-brain barrier.

Fortunately, there are some agents that can penetrate the blood-brain barrier (BBB) and help treat brain metastases. Treatment options are tailored to the individual patient and cancer profile.

Chemotherapy involves the use of drugs that target and kill rapidly dividing cancer cells. Traditional systemic chemotherapy may have limitations in treating brain metastases due to the blood-brain barrier, which restricts the entry of many drugs into the brain.

Normally, the blood-brain barrier is critical in maintaining the brain’s safe internal environment. However, while metastases establish themselves in the brain by crossing that blood-brain barrier, it is that same blood-brain barrier that limits the effectiveness of chemotherapeutic drugs in reaching and targeting brain metastases.

In chemotherapy, the choice of chemotherapeutic drug is usually determined by the primary cancer. While more options are introduced every year, here are some commonly used chemotherapeutic agents:

• Methotrexate: An antimetabolite that interferes with DNA synthesis and repair, it has some ability to cross the BBB and is used in certain types of brain metastases.
• Temozolomide: An oral alkylating agent, it is commonly used in the treatment of primary brain tumors and has shown activity against brain metastases.
• Carboplatin and Cisplatin: Known as platinum-based drugs, these medications have demonstrated efficacy against various cancers, including those that metastasize to the brain. They are often used in combination with other agents.
• Topotecan and Irinotecan: Called topoisomerase inhibitors, these medications have shown promise in the treatment of brain metastases, particularly in combination regimens.

Over the past few decades, considerable research has improved the effectiveness of chemotherapy in the management of brain metastases. At the same time, advances in drug development and delivery techniques have expanded the role of chemotherapy in managing brain metastases.

There are many avenues of treatments available to patients based on their specific cancer and brain metastases. Here are some recent advances in therapeutic options:

• Tyrosine Kinase Inhibitors (TKIs): TKIs target specific genetic mutations in lung cancer and have demonstrated efficacy in managing brain metastases. Examples of TKI medications include osimertinib and alectinib.
• HER2-targeted therapies: These medications target brain metastases that are HER2-positive, which is a receptor found in certain breast cancers. Examples include trastuzumab and lapatinib.

Immune checkpoint inhibitors enhance the immune system's ability to recognize and attack cancer cells.  Examples, such as pembrolizumab and nivolumab, have shown encouraging results in the treatment of brain metastases.

Studies are also exploring combinations of immunotherapy with other treatment modalities, including radiation and chemotherapy, to enhance efficacy.

• Osmotic Blood-Brain Barrier Disruption (BBBD) is a technique that temporarily opens the blood-brain barrier, allowing for increased drug delivery to brain tumors. This approach is being investigated to enhance the effectiveness of chemotherapy in brain metastases.
• Nanoparticle-based drug delivery systems are designed to improve the transport of drugs across the blood-brain barrier. Drugs with this delivery method increase their concentration at the tumor site while minimizing systemic side effects.

Some researchers are also exploring intranasal delivery routes to bypass the blood-brain barrier and deliver drugs directly to the brain.

• Liquid biopsy analyzes circulating tumor DNA in the blood. Liquid biopsy is emerging as a non-invasive method for monitoring treatment response and detecting genetic alterations in brain metastases; medical providers can adapt treatment strategies based on real-time molecular information.
• Molecular profiling identifies specific genetic mutations to better understand a tumor’s particular characteristics, allowing for targeted therapies tailored to the individual patient.

In addition to these options, researchers and healthcare institutions worldwide collaborate every day to accelerate the development of effective treatments for brain metastases.

Ongoing clinical trials explore novel innovative therapies, including oncolytic viruses (viruses that destroy cancer cells), gene therapies, and combination approaches involving different treatment modalities, allowing patients to access cutting edge treatments.

The severity and specific side effects of chemotherapy regimens can vary depending on the type of chemotherapy drugs used, the dosage, and other individual patient factors. Here are some common side effects of chemotherapy for brain metastases:

• Nausea and vomiting
• Fatigue
• Hair loss (alopecia)
• Immunosuppression
• Inflammation and sores in the mucous membranes of the mouth and digestive tract
• Damage to peripheral nerves
• Cognitive changes
• Gastrointestinal issues
• Changes in taste and appetite
• Skin changes
• Fertility issues

As medical technology has advanced, so too has the management of brain metastases evolved to keep pace. From traditional approaches like surgery and radiation, to the promising realm of targeted therapies and immunomodulation, patients now have a broader spectrum of treatment options before them.

For those confronting the complex challenges of brain metastases, the emerging era of precision medicine—medicine tailored to a patient’s individual needs, genes, and environment—coupled with ongoing efforts in clinical research, offers hope for improved outcomes and better quality of life.

As the field of oncology continues to progress, collaboration among healthcare professionals, researchers, and patients will be pivotal in shaping a future where effective, personalized treatments for brain metastases become a reality, then a standard.

• The biggest challenge with chemotherapy for brain metastases remains the blood-brain barrier, which makes it harder for chemotherapeutic drugs to reach and target metastases in the brain.
• Advances in drug delivery, particularly solutions to bypass the blood-brain barrier, are the focus of research efforts around the world.
• Patients have increasingly more options for brain metastases.
• Treatment choices and side effect of treatments can vary based on the brain metastases and patient’s own medical history.

• American Association of Neurological Surgeons (AANS): Metastatic Brain Tumors
• National Cancer Institute (NCI): Brain Tumors
• National Brain Tumor Society: Signs & Symptoms
• CancerCare: Brain Cancer