By Kim Margolin, M.D., FACP, FASCO
The vast majority of people diagnosed with cutaneous melanoma are cured by one or two small surgical procedures done by the dermatologist and surgical oncologist. The dermatologist who suspects melanoma usually performs a shave biopsy that scoops out the suspicious spot, and if it turns out to be melanoma based on the pathologist’s reading under the microscope, sends the patient to the surgeon. The surgeon then cuts a wider swath around the scar to be sure that any remaining tumor is removed and that the margins of melanoma-free tissue around the tumor are adequate (the thicker the original melanoma was, the wider is this swath of tissue). This procedure is called a wide local excision (WLE). Since most melanomas are shallow at the time of discovery and do not involve any lymph nodes or other tissues (see below), this pair of procedures will cure most patients.
A minority of those diagnosed with melanoma will have metastasis—meaning the melanoma will have spread to nearby skin or lymph nodes (local metastasis/Stage III melanoma), or it will have spread to distant visceral sites, such as the liver, lung, bones, or brain (distant metastasis/Stage IV melanoma). At the time of the WLE, these patients’ metastasis may already be discoverable through diagnostic imaging or further biopsy, or the cancer cells may be in the process of spreading and not yet detectable on a physical examination or by a scan.
How melanoma spreads
Melanoma spreads through the lymphatics—tiny invisible vessels that normally carry white blood cells through the body—and this route usually takes melanoma cells to lymph nodes and skin. It also spreads through the blood vessels, which accounts for spread to the visceral sites (liver, lung, bones, brain). Melanomas can spread through both avenues, but certain types of melanoma are less likely to spread through lymphatics and more likely to spread through the bloodstream, such as mucosal melanoma (arising in mucous membranes internally) or uveal melanoma (from the pigmented cells of the eye).
When a melanoma primary tumor and/or the patient have certain risk characteristics (more on this subject, below), the patient may undergo diagnostic imaging to assess whether there is distant spread. This imaging will reveal if there are tumors in the visceral sites. The patient may also undergo a sentinel lymph node biopsy (SLNB) at the time of the WLE. In this operation, one or a small number of lymph nodes are removed to assess whether they contain tumor cells—whether there is local spread. For patients with an elevated risk of recurrence (the melanoma coming back) or with cancerous lymph nodes, the usual treatment recommendation is postoperative adjuvant therapy (additional treatment given after the primary treatment), using immunotherapy drugs or, if BRAF mutation found [see January 2021 In Plain English], targeted therapies, to lower the chance of recurrence either locally near the primary site, regionally in the node site, or at a distance.
The biological basis of melanoma’s spread from a primary lesion with no lethal potential to a metastatic tumor (a cancer that has spread) with potentially fatal consequences has generated innumerable research projects and corresponding articles in the medical literature. Nevertheless, the precise prognostic (predictive) and metastasis-determining elements in each individual’s melanoma are not possible to identify at this time. We have only statistical data to use, and that is hard to apply to individual patients. In other words, we don’t know by looking at your melanoma whether it will spread or not. A technically-detailed explanation of what is known and how it is used in the current development of clinical research to understand risk for melanoma patients is beyond the scope of this article, but most of the factors currently used are unfortunately very low-technology. Certain characteristics of the tumor seen under the microscope can indicate risk, such as the melanoma’s thickness (sometimes called Breslow’s depth) and whether the melanoma is ulcerated (the top layer of skin is not intact). Scans and imaging are used to assess whether a melanoma has already spread to distant sites. And clinical assessments such as whether lymph nodes are “palpable” (swollen and able to be felt) are indications of risk.
The dreaded occurrence of metastatic melanoma, which can have more than a 50% mortality rate, may be found in the regional lymph nodes by the patient or the physician or may be detected on a surveillance scan or ultrasound. Patients can also have small deposits of melanoma in the skin near the original malignant lesion (which is called satellite recurrence) or along the route of travel between the primary and its draining lymph nodes (which is called in-transit metastasis). Patients almost always undergo a biopsy at one or more sites when there is a suspicion of melanoma spread, because the management and the prognostic implications of recurrence and spread are of the utmost importance.
Sites of metastatic disease
Sometimes even a patient with melanoma that has spread can be cured with surgery. Surgery is feasible when the number of metastatic sites is limited (generally no more than two to three separate sites) and can be safely resected (removed) by the surgical oncologist. Customarily, just as for patients with initial high risk of recurrence, patients who undergo surgery for limited metastatic melanoma will also be treated with postoperative adjuvant therapy, using immunotherapy drugs or, if BRAF mutation is found, targeted therapies [covered in In Plain English, January 2021].
Patients who cannot be cured with more surgery, and whose disease must be treated with systemic therapy (oral targeted drugs or intravenous immunotherapy), will be discussed in the rest of this issue of In Plain English.
It is important to remember that you cannot die from melanoma unless it has invaded the body and spread to other sites; in other words, you can only die from Stage III or Stage IV melanoma. And although Stage III itself is rarely lethal, it is possible to succumb to regional metastatic melanoma if the cancerous lymph node(s) cannot be removed safely and if the disease does not respond to therapy. Nodal masses tend to start as small lesions that generally don’t cause lethal compression of a critical structure or other complications like hemorrhage or infection. Nevertheless, with unrelenting growth, such tumors can grow and cause these complications as well as becoming necrotic (dead tumor tissue) with resulting pain, infection, compression of a critical structure (for example, the ureters, which can lead to kidney failure) and blood clots. Besides targeted therapy and immunotherapy, a Stage III patient or a patient with in-transit metastases may be treated with intra-tumoral injections of an inactivated herpesvirus that has been engineered to produce in the tumor a substance that attracts immune cells capable of recognizing and killing tumor. Sometimes the immune reaction resulting from injecting tumors with this virus (TVEC, Imlygic) is so potent that the immune cells can travel to other sites in the body and kill tumors that were not directly injected.
In thinking about how metastatic melanoma can have lethal consequences when it has spread to more distant parts of the body, nearly anything can happen, as melanoma is remarkable in its ability to spread to and establish fatal metastases in just about any part of the body. For example, when melanoma spreads to the liver or lungs, those organs fill up with tumors that eventually block their normal function, which is ultimately fatal to the patient unless one of the systemic therapies can reduce or eliminate those tumors.
Melanoma is also the tumor type with the highest propensity to travel to the brain, where it can cause bleeding, inflammation and pressure on normal structures that result in neurologic deficits. In fact, the single most common site of metastases with lethal outcomes in melanoma patients is the brain. This lethality is in part because the best available therapies for brain metastases—surgery and stereotactic radiotherapy (which delivers very high doses of radiation focused on single, small lesions)—are both limited in the number and size of lesions that can be treated, and these therapies do not prevent the occurrence of new lesions in new sites within the brain. Additionally, whole brain radiation, while useful for selected other malignancies, does not work against brain metastases of melanoma, because the amount of radiation that can be given to the whole brain is insufficient to kill melanoma cells, since they are relatively resistant to radiation. Systemic immunotherapy and targeted therapy are not sufficiently effective in patients who have neurologic symptoms and swelling around the brain lesions, because these patients are treated with steroids to reduce the inflammation, but the steroids reduce the activity of the drugs. The topic of managing patients with melanoma and brain metastases will be covered in greater detail in part two of this two-part series on metastatic melanoma.
Treatment of metastatic disease
The era of successful treatment of metastatic melanoma started with the testing of ipilimumab (Yervoy) in the early 2000s and its approval by the FDA in 2011 for advanced melanoma. Between 22 and 25% of patients who have taken ipilimumab, depending on the mixture of prognostic factors, appear to be cured, and this form of therapy requires only four treatments in three months. While ipilimumab is not accompanied by the typical side effects and risks of chemotherapy like hair loss, nausea, and low blood counts, it can cause side effects related to generalized stimulation of the immune system that results in an attack on normal tissues, a complication that in turn requires immunosuppressive treatment. The successful treatment era continued in 2014 and 2015 when the FDA approved two new forms of immunotherapy related to ipilimumab but possessing greater potency and fewer risks and side effects. When these two drugs—pembrolizumab (Keytruda) and nivolumab (Opdivo)—are used singly, the response rate for melanoma patients is in the 35-40% range, and around 70% of those patients who go into remission appear to have long-term control of metastatic melanoma without relapse. When one of the latter drugs is combined with ipilimumab, the highest durable response rates ever reported—around 55%–can be expected for metastatic melanoma patients, and the cure rate may be as high as 40-45% with these drugs. We don’t always use the word “cure” with certainty, since the drugs are still relatively new, and there remains the possibility of late relapse even in patients who appear to be relapse-free for several years following the completion of therapy. New drugs related to these agents (other forms of what we call “immune checkpoint blockade”) are under development and appear very promising—for example, a combination blend of nivolumab (Opdivo) and the newest drug relatlimab has been approved as Opdualag for metastatic melanoma, with a better response rate than nivolumab and a substantially reduced toxicity compared with ipilimumab plus nivolumab. In addition, completely new designs for the treatment of advanced melanoma and other malignancies are also being investigated.
Treatment of metastatic melanoma that carries a mutation of the oncogene (cancer gene) BRAF has been addressed in a prior In Plain English (January 2021). Of note is that patients with metastatic melanoma who are treated with one of the pairs of targeted oral drugs designed to block the BRAF pathway have an extremely high rate of remission, in the 70-80% range, with additional patients having minor tumor regressions. However, these drugs have almost no cure potential, as resistance emerges during therapy after an average duration of one year, and subsequent therapy is rarely effective. Targeted therapy is generally not favored as the first treatment for metastatic melanoma and is usually reserved for patients who do not achieve long-term remission from immunotherapy. The concept of sequencing targeted therapy and immunotherapy for advanced melanoma was studied in an important randomized trial and summarized in the January 2022 article In Plain English. One exception is patients who have underlying autoimmune diseases that might be exacerbated by the immunotherapy given for melanoma; these patients are generally given targeted drugs as first therapy. Another exception are patients with autoimmune diseases who are dependent on immunosuppressive drugs that lower their responsiveness to melanoma immunotherapy; these patients, if their melanoma has a BRAF mutation, are also generally treated with targeted agents as first therapy.
Chemotherapy, more correctly termed “cytotoxic chemotherapy” to distinguish it from targeted drugs, can induce remissions and sometimes even cures in many other cancers, but cytotoxic agents are rarely used and essentially never provide long-term remissions in melanoma patients. Chemotherapy drugs generally work by direct interference with a critical pathway in malignant cells that provides susceptibility to the drug or a combination of drugs. Most chemotherapies are not specific to the cancer but have general applicability to many different tumor types. Melanoma does not appear to have sufficient susceptibilities to any cytotoxic agents and has only one pathway that can be blocked by BRAF-pathway treatments.
Rare melanoma subsets
We will finish with a few words about the rare melanoma subsets. Acral melanoma (addressed in the March 2021 issue of In Plain English), arises on a patient’s palms, soles, and finger/toenail areas. Acral melanoma has different mutation patterns from common cutaneous melanoma and is less responsive than cutaneous melanoma to the immunotherapies discussed above. However, there are currently no drugs specifically used for patients with acral melanoma, and acral melanoma rarely has BRAF mutations to target, so immunotherapy is the most likely choice of treatment, despite its lack of efficacy. Mucosal melanoma, arising in any of the mucous membranes of the body (mouth, nose, gastrointestinal tract, anus, and vagina), is even more resistant than acral melanoma to the drugs used for cutaneous melanoma and similarly lacks the “druggable” mutations required for targeted therapy. Uveal melanoma, arising in the pigmented tissues of the eyes, tends to metastasize almost exclusively to the liver and is almost uniformly resistant to immunotherapy. We now have a treatment called Terentius (Kimmtrak) for selected patients with metastatic uveal melanoma, a complex drug in which one end attaches to the tumor cell and the other end stimulates the T lymphocytes responsible for immune killing of the melanoma cells. This is a rare melanoma type, and the drug is available to only half of the patients and has a lot of side effects, but it is a good start in the desperate area of finding a treatment for this highly resistant subtype of melanoma. Research continues in this area.
As noted at the beginning of this article, the vast majority of cutaneous melanoma patients will be cured through the process of biopsy and WLE, so metastasis in melanoma can be considered rare, fortunately. But rare is a relative term. Nearly 100,000 cases of invasive melanoma are estimated to be diagnosed in 2022, and in the same year, 7650 patients will succumb to metastatic melanoma. Many patients will be treated with targeted therapies, immunotherapies, or other treatments, and after treatment, a substantial number will be considered melanoma-free. But robust research continues in an attempt to find active and safe treatments for the remaining metastatic melanoma patients who do not respond to treatment, or whose response to treatment is not durable.
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