By Kim Margolin, M.D., FACP, FASCO
Background about melanoma and other malignancies involving the brain
Of all the kinds of cancer in adults, the one with the highest likelihood of spreading to the brain is melanoma. Two other types of cancer are somewhat less likely to involve the brain—lung and breast cancer—but because they are so much more common in the general population, the prevalence of patients with brain metastases from lung cancer and breast cancer is higher than that of melanoma. Melanoma is unfortunately distinguished as being relatively resistant to radiation therapy, especially compared with breast cancer and lung cancers, which are often treated successfully with a variety of forms of radiation. Thus, melanoma has unique challenges that have led to unique solutions, which are finally starting to show success and pave the way for new investigations.
Brief discussion of how melanoma is unique and how it gets into the brain
The major route of spread for any tumor going to the brain is through the bloodstream. Lymphatic vessels, while important in some forms of tumor spread, do not carry cancer cells into the brain. While it may be more common for cancers that involve the lungs to spread to the brain (considering that essentially all blood that goes to the brain and all other organs and parts of the body must also pass through the lungs in order to fill with oxygen), involvement of the brain is by no means dependent on spread to the lungs—unless the cancer is microscopically involving the lungs and not detectible by the usual scans.
Many laboratories and scientists are working on understanding the biological underpinnings of melanoma cells that cause them to go to the brain, settle there, and thrive. Those patients with advanced melanoma who have brain metastases often die of complications in the brain. Probably the most common complication that leads to the patient’s death from melanoma in the brain is bleeding and/or swelling, which cause loss of critical brain functions. Melanoma has a particularly rich blood supply, and these vessels are very fragile and bleed easily, even spontaneously without injury or other causes such as anticoagulation or low platelet count. Melanoma in the brain is often surrounded by swelling (edema), which can require large doses of steroids to reduce the edema and alleviate symptoms such as headache or neurologic deficits. Steroids don’t always work; and furthermore, steroid therapy can be complicated by muscle weakness, opportunistic infections (the ones that take advantage of a suppressed immune system), diabetes, or psychotic behavior. Sometimes control of swelling can be achieved by treatment with drugs that reduce blood vessel growth or leakiness, such as bevacizumab (Avastin), an antibody that is also used in combination treatments for other kinds of tumors.
Ideally, the deep causes of melanoma spreading to the brain will be unraveled by laboratory scientists, and it will be possible to identify patients at high risk for this complication long before it occurs. By understanding these factors, it may become possible to intervene in ways that are not currently available and thus move towards preventing brain metastasis altogether. We already have a large body of literature (published reports from clinical and laboratory science) that tries to explain the brain-seeking behavior of metastatic melanoma. However, many reports focus on just a single or limited number of characteristics that increase the risk of brain metastasis, and we know that the story is far more complex and cannot be explained by studies of single or very few factors. Like so many other phenomena in cancer, it is likely that understanding the likelihood of developing brain metastases will require a complex map or algorithm that integrates multiple independent or partially-connected factors and then tests them in animals and then people.
Detecting melanoma when it has metastasized to the brain
The best way to detect any abnormality in the brain is almost always the MRI, which stands for magnetic resonance imaging. In fact, the imaging device is a very strong magnet that does not cause any radiation exposure, and for the most part, the intravenous contrast material that is injected in order to best delineate all of the brain structures is non-toxic. Brain MRIs very clearly demonstrate the normal brain tissue and a vast number of types of abnormalities that range from blood vessel alterations to infections to benign tumors to malignancies, either primary brain tumors or metastases from cancers starting outside of the brain (like melanoma).
Because melanoma usually spreads to the brain only after it has already been detected in other areas outside of the brain, it is rarely necessary to prove by biopsy that a spot showing up on MRI scan is indeed melanoma. However, there are some exceptions: For example, rare patients have a lesion (spot) in the brain without evidence of spread from a prior melanoma to any other part of the body. Since those patients would not be getting regular scans, they often get diagnosed with a suspicious lesion as a result of going to their doctor with a new neurologic symptom. Even rarer, but at least as important, is a patient who never had any history of melanoma but turns up with a symptomatic brain lesion that requires biopsy for diagnosis as well as sometimes surgery to relieve the neurologic deficit (loss of function). Brain surgery is always done exceedingly carefully to avoid removing any normal brain tissue—and the resulting positive margins (lines where the neurosurgeon has cut to remove the tumor) are generally treated after surgical recovery with a form of intensified but highly localized radiation that is described below.
The most common presentation of melanoma metastatic to the brain has evolved from the evaluation of a patient with a new neurologic symptom or finding on exam to identification of patients on routine brain MRIs that are done as part of their staging evaluation (assessing how far melanoma has spread by doing scans such as CT or PET-CT of the body). This may occur at the time of initial staging or may occur after the patient has failed to achieve long-term benefit from his/her first treatment for advanced melanoma and is about to switch to a later line of therapy.
The role and type of radiation used for brain metastases
Melanoma has long been considered a radiation-resistant malignancy, and nowhere is this more critical than in the brain, where a growing tumor poses life-threatening consequences. Radiation oncologists used to rely on radiation of the entire brain, which had been used successfully for other malignancies due to their sensitivity to radiation and the resistance of normal brain to radiation. Radiating the entire brain could address the grim fact that whenever there is one or a small number of brain metastases, almost inevitably more lesions will follow. The field changed dramatically in the 1990s with the advent of stereotactic radiation or radiosurgery (SRS), a method of directing multiple radiation beams into a single tumor, delivering a very large dose to a small spot, and sparing the surrounding tissue. Several lesions can be irradiated at the same time, and the procedure can be repeated for new lesions, up to a certain point that is determined by the number, size, and location of metastases. And like traditional radiation, it is possible to safely combine SRS to the brain with other forms of therapy, particularly immunotherapy [note—when SRS is given to patients receiving molecularly targeted drugs for melanoma—see In Plain English: What is a “Triplet,” and Why Does it Matter in Melanoma?—it is recommended that the targeted agents be withheld for a few days to avoid excessive toxicity to the surrounding tissues].
Systemic therapy for patients with melanoma and brain metastases
Until 2011, with the approval of the first effective immunotherapy and the first targeted drug against melanoma carrying a BRAF mutation, treatment of the brain was limited to radiation, and the only systemic therapies were chemotherapy agents which had substantial toxicities and almost no activity. Occasional patients derive benefit from temozolomide, a mild chemotherapy used for primary brain tumors that crosses the physiologic barrier between blood and brain but has very low activity against melanoma. In 2012, the first reports came out that demonstrated activity for ipilimumab (Yervoy) against both brain and non-brain metastases in melanoma, and several years later, reports of pembrolizumab (Keytruda) and then the combination of ipilimumab and nivolumab (Opdivo) for patients with melanoma and brain metastases were published. The bottom line with these studies was that, for the most part, patients in good shape without symptoms from their brain metastases and without a dependence on steroids could have the same probability of benefiting from immunotherapy in the brain as they did in the body, and the rate of benefit was the same as for patients without brain metastases at all. For patients with neurologic symptoms and/or dependence on steroid therapy, the rate of response to immunotherapy has been much lower, and this situation remains as a serious unmet need for melanoma patients with brain metastases.
Patients with metastatic melanoma whose tumor carries the BRAF mutation have only a very small increase in their risk of developing brain metastases, and these patients have been treated with the BRAF-targeted drugs that are detailed in a previous issue of IPE. The data for these patients suggests that response in the brain is possible but occurs at a somewhat lower rate than when these drugs are used for patients without brain metastases and that the response to therapy is of shorter duration in the presence of brain metastases. Therefore, just as for patients without involvement of the brain, the use of immunotherapy first, even when the melanoma has a BRAF mutation, is recommended (as for the DreamSeq data, see In Plain English: The Results of DreamSeq), particularly in patients without dependence on steroid. For those who require steroid therapy to control swelling around the tumor(s) or neurologic symptoms, the use of SRS and an attempt to wean the patient off of steroid therapy should be attempted prior to immunotherapy.
In conclusion, the prognosis is looking up for patients with melanoma that has spread to the brain, but there remain many unanswered scientific questions and many unmet clinical needs. Working in this field has provided many opportunities for the discovery of how melanoma behaves and for the development of new treatment strategies. As new drugs continue to be demonstrated effective in this disease, they are likely to contribute to improved treatment outcomes.
Dr. Margolin is a Medical Director of the SJCI Melanoma Program, St. John’s Cancer Institute. She worked at City of Hope for 30 years and also held faculty positions at the Seattle Cancer Care Alliance/University of Washington and at Stanford University. Among her academic achievements were long-term leadership of the Cytokine Working Group, leadership involvement in the Cancer Immunotherapy Trials Network, participation in the Southwest Oncology Group’s Melanoma Committee, and many positions in the American Society of Clinical Oncology and the Society for Immunotherapy of Cancer. Dr. Margolin has reviewed grants for many cancer-related nonprofit organizations and governmental agencies. She has also served as a member of the Oncology Drugs Advisory Committee to the FDA, the American Board of Internal Medicine’s Medical Oncology certification committee, and the Scientific Advisory Committee of the European Organization for the Research and Treatment of Cancer.
Dr. Margolin collaborates with AIM at Melanoma to write the monthly “in Plain English” to provide timely updates on new developments for patients, caregivers, and other individuals with an interest in medical advances in melanoma.
Questions on this article may be submitted to Alicia@AIMatMelanoma.org