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Skin melanoma, one of the most serious forms of skin cancer, poses a significant threat to global health. Most patients present with early-stage disease (skin, lymph node, or skin with lymph node involving). In recent years, several advancements in treatment approaches of early-stage disease have brought hope for those battling this aggressive disease. 

Among these innovations are improved surgical approaches, adjuvant and neoadjuvant therapies.

Before delving into treatment of early-stage melanoma, it is crucial to understand skin melanoma itself. Melanoma arises from the pigment-producing cells (melanocytes) in the skin, and it can appear as a new mole or develop from or in an existing mole.

Prolonged exposure to ultraviolet (UV) radiation from the sun or tanning beds is a leading risk factor for developing melanoma. Other risk factors for melanoma include light skin complexion, family history of melanoma/skin cancer and the presence of many moles on skin. Detecting melanoma early is key for successful outcomes, as advanced stages of the disease are more challenging to manage.

Melanoma diagnosis begins with biopsy of suspicious area of skin, usually done by a dermatologist. Subsequently, a surgical oncologist performs a “cancer surgery” with adequate margins that is usually determined by how deep melanoma had invaded into skin. Once certain depth of invasion is found, lymph node evaluation by a procedure called sentinel lymph node biopsy may be necessary. Upon completion of these procedure, a final pathological stage of melanoma is determined; this allows medical oncologist to assess prognosis and recommend treatments to reduce risk of recurrence.

These treatments are known as adjuvant therapies. Currently, immunotherapy and targeted therapy are commonly used in early-stage melanoma to reduce risk of recurrences. Clinical trials have shown that patients who received adjuvant therapy had better outcomes compared to those who underwent surgery alone. Furthermore, adjuvant treatments can potentially reduce the need for additional surgeries, making it an essential component in comprehensive melanoma care.

 Immunotherapy has shifted the paradigm in cancer treatment in many different types of cancers by harnessing our body's immune system to recognize and eliminate cancer cells. Immune checkpoints are molecules that our body’s immune system uses for its own regulation and appropriate functioning. Cancer cells, however, take advantage of these regulatory pathways to avoid immune recognition, leading to unchecked growth. Development of blocking antibodies toward these immune checkpoints enhances the activity of T cells which then recognize and target cancer cells more effectively. Engineered antibodies knowns as checkpoint inhibitors, such as anti-PD-1 and anti-CTLA-4 antibodies, reinvigorate the immune system to recognize melanoma thus have shown amazing activity in controlling it.

Opdivo (nivolumab) and Keytruda (pembrolizumab) target PD-1 and both are approved for stage 2b-4, whereas Yervoy (ipilimumab) targets CTLA-4, and is approved for node-positive disease in the adjuvant setting. Most used adjuvant therapies (Opdivo, Keytruda) given for one year after surgery have shown to carry low toxicity burden while being very effective decreasing recurrences. Ongoing trials look to add to this approach by making cancer vaccine that are given in combination with immunotherapy, to patient with high-risk early-stage melanoma.

 Roughly, 40-45% of skin melanoma harbor a mutation, called BRAF (BRAF V600 E/K most common) mutation. This mutation allows uncontrolled growth and spread of melanoma. Patients whose melanoma has spread to lymph nodes and who are surgically rendered disease free are candidates for Tafinlar (dabrafenib)/Mekinist (trametinib) given orally in adjuvant setting. This oral combination therapy given for one year after surgery has showed to increase recurrence free survival.

Patients who have melanoma spread to lymph nodes detectable either on physical exam or radiological scans, carry a significant risk of recurrence. These patients are candidates for medical treatments prior to surgical interventions. These medical treatments are known as neoadjuvant therapies. Underlying scientific thought to this approach is that intact tumor cells in skin and lymph nodes provide a better “learning environment” for immune cell functioning to eradicate melanoma to reduce recurrences. It also allows evaluation of tumor's response to a particular therapy before committing to surgery. Additionally, neoadjuvant therapy can downsize large tumors, making them more amenable to surgical removal.

Multiple clinical trials have shown this approach to be very effective. Clinical trial SWOG S1801 has been practice changing by showing advantage of neoadjuvant immunotherapy over adjuvant immunotherapy in lymph node-positive melanoma. In current practice, most of clinical lymph node-positive skin melanomas are treated with this approach. Neoadjuvant therapies mirror those used in adjuvant treatment, with immunotherapy and targeted therapy (used less commonly) being the primary options.

The emergence of adjuvant and neoadjuvant treatments has led to significant changes in ways skin melanoma is treated. Ultimate hope of either of these approaches is to prevent melanoma recurrences and reduce loss of quantity/quality of life.

For more news on cancer updates, research and education, don’t forget to 

Depending on the disease specifics, patients with melanoma may undergo pre- or post-surgical therapies. 

Understanding Adjuvant and Neoadjuvant Melanoma Treatment

Melanoma, a type of skin cancer, has been historically challenging tumor to treat in the advanced setting due to an aggressive nature and resistance to conventional treatments. Current discussions in our clinics with patients who are newly diagnosed with melanoma are filled with hope and promise. These discussions include topics like clinical trials, FDA-approved therapies ranging from target therapies to various modalities of immunotherapies to harness our body’s own abilities to control advance melanoma. Clinical trials that have led to FDA approvals of targeted agents, immunotherapy with check point inhibitors (CPI), with future approval expected for adoptive T-cell therapy, and immTACs (immune mobilizing T-cell receptor against cancer), have improved the prognosis of many with melanoma.

Melanoma, the deadliest type of skin cancer, arises from the uncontrolled growth of melanocytes, the cells responsible for producing melanin pigment in our skin. Though this disease is uncommon (with lifetime risk of 2.6% for Caucasian people, which is 20 times higher than Black people), it leads to significant life loss.

Most early-stage melanoma does not recur, but as the primary melanoma invades deeper to into skin or moves to lymph nodes, its risk of recurrence and spread to other organs post-surgery increases. Once spread beyond skin or to other organs, traditional treatments, such as surgery, chemotherapy and radiation have limited success in advanced melanoma. However, new medications studied in clinical trials and approved by FDA have shifted the treatment landscape. Therapeutic developments have introduced novel approaches, such as targeted agents leveraging mutations in melanoma, immunotherapy beyond checkpoint inhibitors Including adoptive T-cell therapy and ImmTACs.

These innovations have led to prolongation of life for many with advanced melanoma. Ten years ago, less than 10% of the patients with advanced melanoma survived beyond five years; whereas now, roughly 50% of patients diagnosed with melanoma are alive beyond five years.

As smart melanoma cancer cells are, they carry number of genetic mutations. Roughly 40 to 45% of skin melanomas harbor a mutation, called BRAF (BRAF V600 E/K most common) mutation. This mutation allows uncontrolled growth and spread of melanoma. One of the first advances in melanoma treatment has been the development of targeted agents designed to selectively inhibit BRAF molecular pathways and stop uncontrolled growth and spread of melanoma. Three combinations of BRAF and MEK inhibitors have been approved and are very effective in controlling melanoma harboring these BRAF mutations. Unfortunately, after an extended time on these BRAF/MEK inhibitors, patients can develop resistance to this approach.

Ongoing trials are trying to answer the question of how to prevent this resistance from developing to improve outcomes with BRAF mutated melanoma. Additionally, other targets, such as c-KIT and NRAS, NF-1 have also been explored in ongoing clinical trials, but effective therapies remain elusive.

Immunotherapy has shifted paradigm in cancer treatment in many different types of cancers by harnessing our body's immune system to recognize and eliminate cancer cells. Immune checkpoints are molecules that our body’s immune system uses for its own regulation and appropriate functioning. Cancer cells, however, take advantage of these regulatory pathways to avoid immune recognition leading to unchecked growth. Development of blocking antibodies toward these immune checkpoints enhances the activity of T cells, which then recognize and target cancer cells more effectively.

Engineered antibodies knowns as checkpoint inhibitors, such as anti-PD-1 and anti-CTLA-4 antibodies, reinvigorate the immune system to recognize melanoma, and have shown amazing activity in controlling it. Previous therapies (chemotherapy, target therapies) when effective, allowed control of disease for a short while. The most important benefit of checkpoint inhibitors has been their durability of responses that has led to significantly prolonged overall survival in melanoma patients, even those with metastatic disease. Ongoing clinical trials are attempting to answer questions such as:

How long advance melanoma should be treated for?

Who is best suited patient for immunotherapy?

Who will have what type of toxicity for treatment?

Dr. Stephen Rosenberg of the National Cancer Institute is pioneering approach where T cells (immune cells) residing in the tumor (aka tumor-infiltrating lymphocyte; TiL) from a person’s melanoma are surgically harvested, enhanced and expanded outside of the patients and then re-infused. This approach led to improvement in melanoma control for some patients.

Another approach is chimeric antigen receptor (CAR) T-cell therapy, where T cells are engineered to express CARs (homing antibodies) targeting specific melanoma antigens. CAR-T therapy has shown encouraging results in clinical trials and approved in few hematological malignancies. Ongoing trials are evaluating benefit of this approach in metastatic melanoma refractory to other treatments. Nonetheless, challenges remain, including finding ideal target antigens and managing potential adverse events associated with this therapy.

ImmTACs are an innovative approach that aims to tailor cancer treatment to individual patients by identifying and targeting specific tumor antigens (proteins). These tumor antigens (for example gp100 and PRAME in melanoma) serve as a target for T cell engagement with melanoma cells. Simply put, a bispecific antibody (antibody that binds two targets) on one end binds melanoma antigen and other binds and activates T cell. This activity leads to melanoma cell death. Therapy built on this approach as already been approved based on improved overall survival in ocular melanoma.

The field of melanoma treatment has experienced significant breakthroughs with the introduction of targeted agents, immunotherapy, adoptive T-cell therapy, and ImmTACs. These innovative approaches have been possible only with clinical trial participation of courageous patients. While challenges such as treatment resistance and side effects persist, patient participation in ongoing clinical trials and collaborations among scientists, clinicians and industry stakeholders will continue to drive advancements and improve outcomes in melanoma treatment. The future holds great promise for combining these therapies, optimizing treatment sequencing, and identifying predictive biomarkers to ensure personalized and effective treatment strategies for melanoma patients.

Dr. Inderjit Mehmi and Dr. Omid Hamid from the Angeles Clinic, explain how therapies like targeted therapies, immunotherapy and T-cell therapies are improving outcomes for patients with advanced melanoma. 

Experts Give an Overview of the Latest Melanoma Therapies 

Patients with melanoma play a vital role in their own post-surgical care, as one expert explained to CURE®.

“Patients that are coming to see us, once they have (received) a diagnosis of melanoma, they are often very concerned, especially when they learn about the disease and how aggressive it can be,” Dr. Justine V. Cohen, a medical oncologist with Dana-Farber Cancer Institute in Boston, said. “And so, they want to follow up and they want to be seen.”

The provider’s goal, Cohen explained, is to detect any post-surgical recurrence of melanoma as early as possible. The stage of a patient’s disease can provide valuable insight into potential recurrence risk, because, as Cohen explained, “then we can devise a good plan for that patient, how often they need to come back, do they need scans, do they just need a history and physical, how often they should be checking their blood work, etc.”

“Patients should feel empowered to ask about their stage of melanoma,” Cohen said. “And the reason why is because they need to know the risk of recurrence. Because when we know the risk of recurrence, we can say, ‘Well, this is what this is what's likely to happen’ or ‘This is what's not likely to happen.’ So, when patients understand their stage, they understand what their risk is, and they know how often to follow up with their doctor.”

Why Melanoma May Need Treatment After Surgery

The provider’s four standard means of detecting melanoma recurrence, as Cohen explained, are asking the patient if they are experiencing symptoms (such as detecting lumps or bumps, fatigue or generalized symptoms such as a lack of appetite), examining the patient, conducting scans and bloodwork analysis.

Cohen cited a study, published in 2008 in the journal 

 that, as she said, “showed that patients actually detect recurrences better than the other three methods that we have.”

, found that “more than half of melanoma recurrences are self-detected; these patients have the most favorable post-recurrence survival rates because of the type of recurrence detected. The mode of detection is a significant predictor of post-recurrence survival.”

FDA OKs Trial of TIL Therapy KSQ-001EX in Skin, Head and Neck and Lung Cancers

“It's really important for patients to have very open lines of communication with their doctors,” Cohen said. “Because if we don't see patients (often), let's say we see a patient once every six months, that's a long time to go between visits and so we rely on patients calling us if new things pop up between those (visits every) six months. So, I always tell patients to call me (and) that I want to know if they're developing any strange symptoms, like they're losing weight unintentionally or they're more fatigued than usual or they have unusual lumps anywhere, any sort of issues. I want to know about that.”

FDA Approves Opdivo for Post-Surgical Stage 2B or 2C Melanoma

Patients with melanoma play a vital role in their own post-surgical care, as one expert from Dana-Farber Cancer Institute explained to CURE®.

Communication Between Patients, Doctors Crucial After Melanoma Surgery

Interview with Dr. Cohen on melanoma surgery 

What's the Plan for Patients With Melanoma After Surgery? 

Patients with melanoma that is fully resectable (meaning it can be removed via surgery) and their care teams need to remain vigilant in case of possible disease recurrence or metastasis (when cancer spreads to other parts of a patient’s body).

“Patients often worry that there's going to be a new melanoma that occurs on their skin and so they're checking their skin very diligently,” Dr. Justine V. Cohen, a medical oncologist with the Dana-Farber Cancer Institute in Boston, told CURE®. “And that is true. Once a patient has a melanoma, there is about a 10% chance that they will develop another melanoma in their lifetime. And they should be very cautious in the sun; we say don't go out during the hours of 10 a.m. to 4 p.m. in direct sunlight without protection (and) without wearing sun protection and sunscreen and a wide-brimmed hat and long sleeves and long pants.”

Rare Immune Cell May Predict Immunotherapy Response in Melanoma

But, Cohen cautioned, risks are present inside a patient’s body as well as on their skin.

“When we talk about recurrence of melanoma, we actually worry more about what we cannot see, what's on the inside,” Cohen said. “And so, it's true that a patient can develop another melanoma on their skin, but we worry about that melanoma’s risk of metastasizing. So, the cells leak out and they travel to the lungs or the liver or the brain and you can't see those. And that's why it's important to follow up with an oncologist because we might have ways of detecting that by asking questions, by doing physical exams, by checking scans and by checking bloodwork.”

Standards of post-surgical care and monitoring differ by what stage of melanoma a patient has had, as Cohen explained.

“Depending on the depth of their melanoma and the involvement with lymph nodes or not, that will determine the surveillance plan and/or adjuvant (post-surgical) treatment plan,” Cohen said. “So adjuvant treatment is giving therapy systemic therapy throughout the body in the post-surgical setting, in order to reduce the risk of it coming back.”

Cancer Vaccine Plus Keytruda Reduces Risk of Recurrence or Death in Melanoma

After surgery, they see the surgeon and they almost always see a medical oncologist. The medical oncologist will determine if they have a stage 1, 2 or 3 melanoma or (stage) four that was still able to be surgically removed, and that medical oncologist will determine the plan. (The) first question is, “What is their risk of recurrence, and do they need a therapy to reduce that risk of recurrence?”

If they don't (need adjuvant therapy), they will move into what's called a surveillance plan. And that surveillance plan is dependent on the stage. So, (patients with) stage 1 melanomas, for example, do not get scans, they don't get CT scans or PET scans, but (for patients with) stage 2 and 3 melanomas, we often do CTs or PET scans in in our surveillance. Most patients, though, are seen by the oncologist anywhere from one to four times a year when they're in surveillance.

Transcript has been edited for clarity and conciseness.

“When we talk about recurrence of melanoma, we actually worry more about what we cannot see, what's on the inside,” Dr. Justine V. Cohen of the Dana-Farber Cancer Institute told CURE®.

What’s the Plan for Patients With Melanoma After Surgery?

Even after melanoma is completely removed, some patients may still need to go on drugs to prevent their cancer from returning.

In a recent interview with CURE®, Dr. Craig Devoe, associate professor of Medicine at the R.J. Zuckerburg Cancer Center, explained the use of post-surgical treatment, and how melanoma became the “poster child” for immunotherapy.

Post-Surgical Opdivo ‘Just Makes Sense’ for Stage 2B, 2C Melanoma

 Can you explain why we still need to treat cancer that has been completely surgically removed?

: There's always a risk with every cancer —breast cancer, lung cancer, colon cancer, and melanoma in this case — that some of the disease cells could migrate down into the local tiny blood vessels or lymph vessels, and then make their way outside of the region of where the surgery was. And in doing so, we can't see them on PET scans or CT scans, but they can then start to grow into a small tumor or in a larger tumor over time, (that is) distant from the original site.

So we give prevention therapy, we call it adjuvant therapy, to mitigate that risk. Various staging systems are used for the different cancers, to indicate what the risk might be. And if you exceed a certain risk threshold, you know, we might recommend employing some adjuvant prevention therapy for you for that situation.

How has immunotherapy affected the adjuvant treatment of melanoma?

Immunotherapy itself was designated a breakthrough of the year in 2013 by 

, and since then, it's lived up to the name and in that it's been a paradigm shift in how we treat patients. Historically, we've used chemotherapy, surgery and radiation to treat patients with tumors. But immunotherapy gives us a fourth modality or fourth weapon against it.

The interesting thing about it is that it utilizes the the patient's own immune system to attack the tumor, as opposed to, instilling medications that directly kill cancer cells or radiate cancer cells or remove them physically, it's more of a stimulant to the immune system to allow the immune system to attack, kill and put the cancer into remission, and in many cases, cure it as well.

Opdivo (nivolumab) was recently approved for the post-surgical treatment of certain patients with melanoma. Can you explain how this drug works?

We call (Opdivo) a checkpoint inhibitor, a checkpoint is an area in the immune system where the immune system meets the cancer cell. And there are proteins that interact that shut down the immune system from attacking the cancer cell. Those, those immune cells are called T cells or T lymphocytes. Many people are familiar with T cells and immune cells from COVID, and a lot of stuff in the news these days.

The drug actually inhibits the interaction of this kind of lock and key mechanism that shuts down the T cell and allows that T cell to awaken recognize the tumor as a malicious entity, and then go ahead and attack it. And it's really effective in doing that melanoma is in essence, the poster child for this kind of (immunotherapy) treatment and was really developed in melanoma first far ahead of anything else. And primarily because melanoma is has so many mutations in it, genetically that have made it so resistant to chemotherapy. Number one, that chemotherapy doesn't really work. Number two, (there are) historical anecdotes of experiences of patients going into sort of spontaneous remissions and things like that had been documented for years suggesting, a role of the immune system at play. And so, so the immune system was really looked at strongly in melanoma too, you know, as a way to as a way to treat melanoma as opposed to the kind of the standard chemo therapies that that really weren't all that effective.

An expert discusses why patients with melanoma may undergo treatment even after their tumor was surgically removed, and how melanoma became the “poster child” for immunotherapy. 

Why Melanoma May Need Treatment After Surgery 

Patients with stage 4 melanoma experience more time toxicity, as they are expected to attend more in-person doctor visits for optimal survival, according to an expert.

Time toxicity, defined by Dr. Timothy Hanna, is an unintended effect in a person’s life, particularly with their time.

Hanna is a radiation oncologist and health services researcher at Queen’s University in Kingston, Ontario, Canada, who specializes in skin cancer treatments, and co-authored a study that was published on 

His research determined that patients with stage 4 melanoma experience more time toxicity because of the amount of time taken away from their everyday life to attend in-person appointments to receive procedures, such as biopsies and surgeries, and drug therapies and radiation.

“The time that (patients) could spend with family, fishing, going to restaurants and enjoying their everyday life is taken away from them to some degree because of the time burden and (doctor) visits that are required in order to gain these survival benefits from the treatments,” Hanna explained in an interview with 

Hanna and co-authors of the study found that patients with stage 4 melanoma were “spending more than one day per week on health care-related contacts.”

Types of Skin Cancer and Their Treatments

“So that’s really important. I think (it’s) valuable information for people who are diagnosed with advanced stage 4 melanoma to know about,” said Hanna. “It’s nice to know that with these new drugs, the chances of living longer, is much better. So, there is this time investment, but thankfully, that time investment hasn’t really gotten any larger compared to how it used to be. So, for that same investment, we’re getting essentially a greater return because of the possibility of longer survival.”

New cancer treatments are often accompanied by many health care visits, you know, we need visits for imaging for seeing the specialist for blood tests. We need visits for medical procedures, like biopsies, surgeries, visits for these expensive new drug therapies, radiation and this can take up a lot of a person's time.

Now, if we're talking about a therapy where this is a lifesaving therapy and it's an earlier stage disease, investing a few months of your time, in order for your life to be saved, would always be worthwhile, you could say. But, when we start thinking about people with more advanced cancers, for example, those with stage 4 disease, such as stage 4 melanoma, in some cases, they may only have a few months or years to live. And so, when we start to think about the time burden that all of these visits placed upon them, this is something that is now called in by many people time toxicity, meaning that this is an unintended effect on a person's time that has, in the patient's perspective, often ill effects. So, the time that they could spend with family, fishing, going to restaurants and enjoying their everyday life, is taken away to some degree because of the time burden and the visits that are required in order to gain these survival benefits from the treatment.

So, what is called time toxicity doesn't specifically affect someone's survival, but it does impact the usefulness of the time that someone might have left. So, if you only had say, three months of life left and half of that was spent on the visits to hospital, those gains and survival from these new expensive drugs might not be, from the patient perspective, worth it. They might decide it's totally worth it. But the information that we can gather and describe for patients under this concept called time toxicity provides information that can help patients and their families decide on the value that they place on the benefits of treatment.

The notion of ‘time toxicity’ causes patients with stage 4 melanoma to have less available time in their everyday lives because of appointments and treatments.  

‘Time Toxicity’ and its Effect on Patients With Stage 4 Melanoma

This summer was a busy time in the oncology space, with multiple therapies gaining Food and Drug Administration (FDA) approval. To gain approval, the therapy must show that it is safe and effective in its intended use and can be manufactured to federal quality standards, according to the FDA’s website.

Here’s a look back at the therapies for solid cancers that gained FDA approval this summer. 

Skin/Melanoma

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