Lindsay Cook, PharmD is a board-certified consultant pharmacist.

Adjuvant therapy for melanoma refers to the use of treatments after surgery to reduce the risk of cancer recurring (or at least delay it) and hopefully improve survival. It is usually recommended for high-risk melanomas including tumors that are stage IIIB and stage IIIC but may also be used in other settings as well.

From the mid-1990s to 2015, the only option was interferon, which had only slight benefits on survival. Since 2015, first Yervoy (ipilimumab) and then Opdivo (nivolumab) and Keytruda (pembrolizumab) have been evaluated and found to significantly improve recurrence-free survival. For people who have tumors with BRAF mutations, the combination of Tafinlar (dabrafenib) and Mekinist (trametinib) can also reduce recurrence risk.

Despite the potential to reduce recurrence risk and improve survival, adjuvant therapy for high-risk melanomas, many people who are eligible for treatment are unaware of this option. Learn about when adjuvant therapy is recommended, the advantages and disadvantages of different treatments, and what to consider when making a decision.

When melanoma is discovered before it has spread to distant regions of the body (before it reaches stage 4), surgery offers the chance for a cure. Unfortunately, some melanomas have a tendency to recur (come back) even after successful surgery. When this happens, it's thought that some cancer cells were left over after surgery, but too few to be detected with the imaging tests we currently have available.

The chemotherapy sometimes prescribed after breast cancer surgery is a form of adjuvant therapy many people are familiar with.

As with adjuvant therapy for melanoma, the treatment is designed to lower the risk of recurrence after primary treatment (surgery).

Even though it's long been known that melanoma can recur, unlike breast cancer, effective and relatively well-tolerated therapies to reduce recurrence are a much more recent advancement.

Whether or not adjuvant therapy is recommended depends on the stage as well as other characteristics of the tumor.

High-risk melanomas (those that have a significant risk of returning) include those that:

Whether or not adjuvant therapy is recommended varies with the stage of the disease, but it's important to note that within each stage there can be many different types of melanoma as not two tumors (even tumors of the same stage) are identical. For this reason, a doctor may recommend adjuvant therapy for an earlier stage melanoma that is concerning or, instead, recommend foregoing adjuvant therapy with a higher stage tumor.

With very early stage tumors, such as those that are stage I and stage IIA, surgery is usually curative, and adjuvant therapy would not be recommended (the toxicity of adjuvant therapy would greatly outweigh its potential benefit).

In contrast, people who have stage IIIB or stage IIIC (based on version 7 of staging guidelines) have a very high risk of recurrence. Despite removal (complete resection) of the cancer, only 32% of people with stage IIIB and 11% of people with stage IIIC survived for five years after surgery without a recurrence. In this case, adjuvant treatment to reduce recurrence likely significantly improves survival, and the benefits of adjuvant therapy would usually outweigh the risks.

Adjuvant therapy (with Opdivo) is also approved for people with stage IIIA melanoma who have at least one micrometastasis to lymph nodes.

There is a group in between these two stages where it's still uncertain whether adjuvant therapy is beneficial or not, such as tumors that are stage IIB, stage IIC, or some that are stage IIIA. With these tumors, there is an increased risk of recurrence, but the risk is often less than 20%. Treatment with interferon has not been shown to affect survival, but immunotherapy or targeted therapy may, and clinical trials are in progress evaluating the possible benefit.

People who have tumors that fall in this category may wish to talk to their doctors about the option of participating in one of these trials.

In addition to the stage, other factors that are noted when considering adjuvant therapy include age, the presence of other medical conditions (co-morbidities), the ability of a person to tolerate treatment, and patient preference with regard to treatment.

In 1996, the first adjuvant treatment, interferon alpha2b was approved for melanoma. Given as a high dose (but not low dose), interferon had some benefit in reducing recurrence risk, but only minimal effects on overall survival.

The effectiveness of adjuvant therapy took a leap beginning in 2015 with the approval of the first immunotherapy drug. There are now three different immunotherapy drugs as well as targeted therapy (a combination BRAF inhibitor and MEK inhibitor) approved as options, and interferon is now rarely used in this setting, at least initially. In addition, other options are being evaluated in clinical trials.

While the use of immunotherapy and targeted therapy for adjuvant treatment of early-stage melanoma is relatively new, these drugs were previously approved to treat metastatic (stage IV) melanoma, and therefore doctors using these medications are very familiar with their side effects and risks.

There are several different types of immunotherapy, which are drugs that work by using the immune system, or principles of the immune system, to fight cancer. Interferon is a cytokine (immune system modulator) that works by accentuating the ability of immune cells to fight cancer and was the mainstay of adjuvant therapy from its approval in 1996 until the approval of the first checkpoint inhibitor in 2015.

There are now three checkpoint inhibitors that may be used as adjuvant therapy. These drugs work by essentially "taking the mask off" of cancer cells so that the immune system can recognize them and attack. While it may feel disconcerting using a "new" drug, these medications have previously been used with metastatic (stage IV) melanoma as well as other types of cancer.

Yervoy (ipilimumab) was the first checkpoint inhibitor approved as adjuvant therapy for melanoma in 2015 and was shown to significantly prolong recurrence-free survival when compared with a placebo. For adjuvant therapy, it is now usually replaced by Opdivo or Keytruda, but may still be used for melanomas that progress while being treated with these drugs.

A 2017 study published in The New England Journal of Medicine compared the use of Opdivo (nivolumab) to Yervoy for adjuvant therapy.

It was found that Opdivo resulted in significantly longer recurrence-free survival than Yervoy with a lower incidence of adverse effects. For this reason, Opdivo became the preferred checkpoint inhibitor to use for adjuvant therapy.

In a follow-up, Opdivo also appeared to have a sustained benefit relative to Yervoy, and this benefit was present regardless of the stage of melanoma, biomarker tests that predict response to checkpoint inhibitors (PD-L1 expression), and whether or not a BRAF mutation was present.

Keytruda (pembrolizumab) is now also an option for adjuvant therapy. A 2018 study in The New England Journal of Medicine looked at the benefits and side effects of Keytruda compared with a placebo for stage III melanoma after surgery. Similar to Opdivo, Keytruda led to a significantly longer recurrence-free survival with no new toxic effects.

An alternative to immunotherapy is available for the roughly 50% of people with cutaneous (skin-related) melanoma that contains a BRAF mutation. Targeted therapies work by targeting specific pathways in the growth of cancer cells, and due to this "precise" treatment (precision medicine), the drugs often have significantly fewer side effects than chemotherapy drugs.

The currently approved treatment is a combination of the BRAF inhibitor  Tafinlar (dabrafenib) and the MEK inhibitor Mekinist (trametinib). Some researchers have argued that the effects of targeted therapy may be more transient than immunotherapy, although a 2018 study in the Journal of Clinical Oncology did find an extended benefit to this regimen.

In contrast to the continued use of targeted therapy with metastatic melanoma (targeted therapies control but do not cure the disease), the treatment is continued for only one year when used as an adjuvant treatment. (Possible advantages and disadvantages of these different treatments are discussed below.)

Since treatments are advancing rapidly for melanoma and since every treatment now approved was once studied in a clinical trial, it's recommended that clinical trials should be considered for people with most stages of melanoma. In addition to studies looking at combinations of immunotherapy drugs, lower doses of immunotherapy drugs, and more, new therapies such as adjuvant vaccines are also being evaluated. In addition, the use of these treatments before surgery (neoadjuvant therapy) is being looked at as a potential option.

As with any medication, treatments used as adjuvant therapy can have side effects and interactions.

The side effects of checkpoint inhibitors can vary with the drug, and as noted above, tend to be more severe with Yervoy than with Opdivo or Keytruda.

The most common side effects include a rash, diarrhea, cough, nausea, and fatigue, though serious reactions may sometimes occur.  These problems can sometimes become severe or life-threatening and can lead to death.

Endocrine disorders such as hypothyroidism are also common. It appears that these drugs do not work as well for some people who are also treated with steroids or some antibiotics. People who have a history of autoimmune disorders, people who are transplant recipients, or those who have a poor performance status may not be good candidates for these drugs.

Common side effects of the combination of  Tafinlar and Mekinist include a fever, rash, headaches, diarrhea, and joint aches. More serious adverse reactions sometimes occur and can include bleeding or perforation of the intestines or other bleeding problems, blood clots, heart failure, and eye problems.

There are two decisions that people will need to make along with their doctors: whether to receive adjuvant therapy or not and which drug to use if the answer is "yes."

It's important for people to work with their doctor so they thoroughly understand both the benefits and risks associated with treatment. Adjuvant therapy can reduce the risk of recurrence, but also increases side effects. While general guidelines are looked at by stage, these factors vary with individual people and individual tumors.

Personal preference is also an important consideration. Some people are willing to tolerate any side effects for the chance to improve survival, and others preferring to have a better quality of life even if the risk of recurrence is greater.

There is currently controversy over the ideal adjuvant treatment for people who have a BRAF mutation (BRAF V600E or BRAF V600K). At the current time we only have separate studies showing the effectiveness of both immunotherapy and targeted therapy, but no studies comparing the two options as far as effectiveness or side effects. The individual studies are difficult to compare as some studies included people with stage IIIA melanoma and others did not.

Since immunotherapy has a more durable response than targeted therapy in stage IV melanoma (immunotherapy may result in continued control of a tumor even after it is stopped, but with targeted therapy, the tumor is only controlled as long as the treatment is continued) some physicians prefer immunotherapy for patients with or without a BRAF mutation. Others argue that targeted therapy may work differently as an adjuvant treatment and some research suggests this is the case.

Looking at the response from another angle, some physicians consider the natural history of the disease and the fact that many of these cancers recur even with adjuvant therapy. In this scenario, it's been argued by some that targeted therapy be used as the adjuvant treatment (since it may be curative as an adjuvant treatment but isn't as a treatment for metastatic melanoma).

How the Medication Is Taken

The way the medication is used is sometimes important for people in choosing an option. Tafinlar and Mekinist are taken orally every day, whereas the immunotherapy drugs are given intravenously (and require traveling to the infusion center) every two weeks to four weeks.

Some people may tolerate the side effect profile of one treatment over another, or be more concerned about short term or long term side effects. Opdivo (nivolumab) usually causes less toxicity than  Tafinlar and Mekinist, but Opdivo is more likely to cause permanent toxicity. Overall, around 10% of people using either immunotherapy or targeted therapy stop the medication due to side effects.

There are also cost differences (and insurance coverage) that may play a role in the decision.

Medicine is changing very rapidly, and though it's encouraging that there are now many more options for treating melanoma, there are also more decisions to be made with regard to treatment. It's important to be your own advocate in your care and to ask questions. Getting a second opinion has never been more important, and many people elect to see physicians who specialize in melanoma at one of the larger National Cancer Institute-designated cancer centers.

American Cancer Society. Melanoma skin cancer stages.

Food and Drug Administration. Prescribing information: Keytruda.

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By Lynne Eldridge, MD  Lynne Eldrige, MD, is a lung cancer physician, patient advocate, and award-winning author of "Avoiding Cancer One Day at a Time."

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