One in five people in the United States will develop skin cancer over the course of their lifetime. Basal cell skin cancer is the most common type of skin cancer, followed by squamous cell skin cancer and melanoma.

Treatment Approaches for Advanced Basal Cell and Squamous Cell Skin Cancer

At the time of diagnosis, most cases of basal cell skin cancer (BCC) and squamous cell skin cancer (SCC) have not spread from their original locations and are managed with local treatments, including the use of topical (applied directly onto the skin) medications or surgical removal of the tumor.

Mohs micrographic surgery, a precise surgical technique, is often used to treat BCC and SCC that appears on the head and neck. This is a “skin-sparing” technique, in which pieces of skin are progressively removed at the site of the tumor and examined under a microscope until only cancer-free tissue remains.

In certain cases, surgery may be difficult or impossible. Radiation therapy may be considered in certain situations; for example, if neither surgery nor a topical medication is an option, or if the skin cancer is in a cosmetically sensitive area.

Even though these types of skin cancers are very common, relatively few evolve into cases that require more intensive treatment. In advanced cases of BCC and SCC, surgery or radiation may not be an option. In these situations, the use of oral (by mouth) or intravenous (through a vein) drugs is often considered as a way to treat the cancer.

Advanced Basal Cell Skin Cancer

Several years ago, researchers discovered that more than 90 percent of BCCs have certain gene mutations (changes) in what is called the “Hedgehog pathway.” These changes activate the growth of cancer cells and allow for their survival. Drugs have been designed to target mutations in the Hedgehog pathway.

Vismodegib (Erivedge) and sonidegib (Odomzo) are Hedgehog pathway inhibitors approved by the U.S. Food and Drug Administration (FDA) to treat advanced BCC. These drugs are used in cases where the BCC has spread to other parts of the body, recurred (returned) after surgery or cannot be treated with surgery or radiation. Hedgehog inhibitors are sometimes used before surgery to shrink the size of a tumor, making surgery an easier process and increasing its chance of success.

Advanced Squamous Cell Skin Cancer

There have not been many clinical trials conducted on advanced SCC, as it is a rare condition. There is much more data available on squamous cell cancer of the mouth and throat, and the FDA has approved the targeted therapy cetuximab (Erbitux) for those cancers. Cetuximab, which is given intravenously, is also approved for the treatment of certain types of colorectal cancer. By attaching to a structure on the cell called the epidermal growth factor receptor (EGFR), cetuximab can block one of the signals that tells a tumor to grow.

If a drug has been approved by the FDA for one use, doctors may prescribe it for other conditions. As clinical trials have shown that cetuximab can be effective in treating advanced SCC of the skin, it is sometimes prescribed to treat people whose tumors cannot be surgically removed or treated with radiation.

Chemotherapy drugs, given orally or intravenously, can slow the spread of advanced SCC. In some cases, they may shrink tumors enough so that other treatments, such as surgery or radiation, can be used. Side effects of chemotherapy can be significant, so it is generally used in cases where other treatments have failed or are not an option.

In September 2018, the FDA approved cemiplimab-rwlc (Libtayo) for the treatment of people with metastatic cutaneous squamous cell carcinoma (CSCC) or locally advanced CSCC who are not candidates for surgery or radiation. Cemiplimab-rwlc, an immunotherapy, is the only drug currently approved for the treatment of skin SCC. Immunotherapy with cemiplimab is now often the first-line (initial) treatment for advanced skin SCC.

Melanoma is considered to be the most serious type of skin cancer. It develops in the cells that produce melanin, the pigment that gives color to skin, hair and eyes. Most cases of melanoma are diagnosed at an early stage, after a tumor appears on the skin. In the majority of people, the melanoma is effectively treated by the removal of the tumor.

Advanced (metastatic) melanoma has spread from where it originated to another part of the body, including lymph nodes or other organs. Deciding what treatment option is best is based on factors unique to the individual, including their health history, energy level, where the cancer appeared initially and where it appears currently. Factors specific to the melanoma itself, such as whether the tumor has a mutation in the BRAF gene, also influence treatment options.

As there are a number of options for treating advanced melanoma, it’s important for people to consult with their doctor to understand what treatment may be most effective for them.

Immunotherapy in the Treatment of Advanced Melanoma

Our immune system is constantly working to keep us healthy. It recognizes and fights against danger, such as infections, viruses and growing cancer cells. In general terms, immunotherapy uses our own immune system as a treatment against cancer.

There are several immunotherapies approved to treat advanced melanoma:

  • Interferon (Intron A, Sylatron). In 1995, the FDA approved interferon as an adjuvant (post-surgery) therapy for people whose advanced melanoma tumors were surgically removed. The use of interferon in these circumstances may stop the growth and spread of any remaining melanoma cells. Interferon is not used as frequently today as it was in the past, because newer and more effective treatments are now available.

  • Aldesleukin (interleukin-2, Proleukin). Since the late 1990s, aldesleukin has been used as a treatment for advanced melanoma. Given intravenously, aldesleukin helps the body’s immune system shrink and destroy tumors more effectively. As is the case with interferon, aldesleukin is not used as frequently today as a standalone treatment as it was in the past.

  • Ipilimumab (Yervoy). Ipilimumab was approved by the FDA in 2011 for the treatment of advanced melanoma. Ipilimumab binds onto CTLA-4, a protein that inhibits immune system cells (called T cells). By blocking the action of CTLA-4, ipilimumab is thought to help the immune system destroy melanoma cells. Ipilimumab is given intravenously.

  • Pembrolizumab (Keytruda). In 2014, pembrolizumab was approved for the treatment of advanced or unresectable (unable to be removed) melanoma. In February 2019, the FDA expanded the approval of pembrolizumab to include adjuvant treatment of melanoma that has lymph node involvement. Given intravenously, pembrolizumab blocks the PD-1 cellular pathway (a pathway that inhibits the body’s immune system from working properly).

  • Nivolumab (Opdivo). Like pembrolizumab, nivolumab works by blocking the PD-1 pathway and is also given intravenously. Nivolumab was approved for the treatment of advanced melanoma in 2014. In 2017, the approval was extended for the adjuvant treatment of melanoma that has lymph node involvement.

  • Talimogene laherparepvec (Imlygic). This drug, referred to as TVEC, is injected directly into the melanoma lesions, where it can cause cancer cells to rupture and die. As TVEC may also improve the immune system’s response to cancer, melanoma lesions that were not injected with the drug also sometimes shrink or disappear.

  • Ipilimumab and nivolumab. This drug combination is approved for the treatment of people with advanced melanoma. It is designed to block the actions of both CTLA-4 and the PD-1 pathway.

Targeted Therapy in the Treatment of Advanced Melanoma

Targeted therapies are designed to inhibit specific cell mechanisms important for the growth and survival of tumor cells. People who may benefit from targeted therapies have specific DNA changes (called driver mutations) that allow cancers to develop and grow. The most important known driver mutation in melanoma is the BRAF mutation, with up to 50 percent of melanomas having this mutation.

A number of targeted therapies have been approved by the FDA for the treatment of melanoma with a BRAF mutation:

  • Vemurafenib (Zelboraf). In 2011, the FDA approved vemurafenib, a drug that inhibits the “signal transduction” pathway in people with a BRAF gene mutation. Vemurafenib can help slow or stop the spread of melanoma cells.

  • Dabrafenib (Tafinlar). In 2013, the FDA approved dabrafenib, which targets the BRAF gene mutation in the same way as vemurafenib.

  • Trametinib (Mekinist). Trametinib was approved by the FDA in 2013 to treat people with advanced melanoma that cannot be removed by surgery. In 2014, the approval was extended to include use in combination with dabrafenib. Trametinib blocks a protein called MEK, which is “switched on” by the BRAF gene mutation. In April 2018, the combination of dabrafenib and trametinib was granted FDA approval for the treatment of melanoma that had spread to the lymph nodes and which has a BRAF mutation.

  • Cobimetinib (Cotellic). In 2015, the FDA approved cobimetinib for the treatment of people with unresectable or advanced melanoma with a BRAF mutation, for use in combination with vemurafenib.

  • Encorafenib (Braftovi) and binimetinib (Mektovi). In 2018, the FDA approved the combination treatment of encorafenib (a BRAF inhibitor) and binimetinib (a MEK inhibitor) for the treatment of people with unresectable or advanced melanoma with a BRAF V600E or V600K mutation.

Studies have shown that the combination of a BRAF inhibitor and a MEK inhibitor often results in the best outcomes, and with reduced side effects.

All cancer treatments can cause side effects. It’s important that you report any side effects you experience to your health care team so they can help you manage them. Report them right away—don’t wait for your next appointment. Early reporting can help improve your quality of life and allow you to stick with your treatment plan. It’s important to remember that not all people experience all side effects, and some people may experience side effects not listed here.

Side Effects of Chemotherapy

The side effects of chemotherapy depend on the type and dose of drugs given and the length of time they are used, and can include:

  • Achiness
  • Nausea/vomiting
  • Hair loss
  • Increased risk of infection (from having too few white blood cells)
  • Easy bruising or bleeding (from having too few platelets)
  • Changes in memory or thinking
  • Peripheral neuropathy (numbness or tingling in hands and feet)

Side Effects of Radiation Therapy

Changes to the skin are the most common side effects of radiation therapy. The changes can include dryness, swelling, peeling, redness and blistering—similar to a severe sunburn but usually occurring much more gradually. If a reaction occurs, contact your health care team so the appropriate treatment can be prescribed. It’s especially important to contact your health care team if there is any open skin or painful area, as this could indicate an infection. Infections can be treated with an oral antibiotic or topical antibiotic cream.

Side Effects of Targeted Therapy

Targeted therapy doesn’t have the same effects on the body as chemotherapy drugs, but it can still cause side effects. Side effects of targeted therapies can include fevers, sun sensitivity, diarrhea, liver problems (such as hepatitis and elevated liver enzymes), nerve damage, rashes, high blood pressure and problems with blood clotting and wound healing.

Side Effects of Immunotherapy

Immunotherapy travels through the bloodstream, helping to prompt an immune response. Sometimes the immune system may attack healthy cells as well as cancer cells, and certain side effects may be experienced.

Common side effects include fatigue, decreased appetite, skin rash and lightening of the skin. Other less common side effects include shortness of breath or frequent episodes of diarrhea. Immunotherapy can also affect the thyroid gland, adrenal gland or pituitary gland. Blood work is routinely taken and symptoms that may be associated with glandular issues are closely monitored while patients are on immunotherapy.

General Side Effects

There are certain side effects that may occur across different treatment approaches. Following are tips for managing these side effects. Your health care team may have additional guidance for your specific treatment type.

Managing Digestive Tract Symptoms Nausea and vomiting

  • Eat small, frequent meals.
  • Avoid food with strong odors, as well as overly sweet, greasy, fried or highly seasoned food.
  • Eat meals cold or at room temperature, which often makes food more easily tolerated.
  • Having something in your stomach when you take medication may help ease nausea.

Diarrhea

  • Drink plenty of water. Ask your doctor about using drinks such as Gatorade, which provide electrolytes. Electrolytes are body salts that must stay in balance for cells to work properly.
  • Over-the-counter medicines such as loperamide (Imodium A-D and others) and prescription drugs are available for diarrhea but should be used only if necessary and with your health care team’s knowledge and approval. If the diarrhea is bad enough that you need medicine, contact a member of your health care team.
  • Choose foods that contain soluble fiber, like beans, oat cereals and flaxseed, and high-pectin foods such as peaches, apples, oranges, bananas and apricots.
  • Avoid food high in refined sugar and those sweetened with sugar alcohols such as sorbitol and mannitol.

Loss of appetite

  • Eating small meals throughout the day is an easy way to take in more protein and calories, which will help maintain your weight. Try to include protein in every meal. Nutrition shakes or protein drinks are a way to add calories to your daily diet.

  • To keep from feeling full early, avoid liquids with meals or take only small sips (unless you need liquids to help swallow). Drink most of your liquids between meals.

  • Keep high-calorie, high-protein snacks on hand such as hard-boiled eggs, peanut butter, cheese, ice cream, granola bars, liquid nutritional supplements, puddings, nuts, canned tuna and trail mix.

  • If you are struggling to maintain your appetite, talk to your health care team about whether appetite-building medication could be right for you.

Managing Pain

There are a number of options for pain relief, including prescription and over-the-counter medications. It’s important to talk to a member of your health care team before taking any over-the-counter medication to determine if it is safe and will not interfere with your treatment. Many pain medications can lead to constipation. Your doctor can recommend over-the-counter or prescription medications that help to avoid or manage constipation.

Physical therapy, acupuncture and massage may also be of help in managing your pain. Consult with a member of your health care team before beginning any of these activities.

Managing Fatigue

Fatigue (extreme tiredness not helped by sleep) is one of the most common side effects of many cancer treatments. If you are very fatigued while on treatment, your doctor may lower the dose of the drug(s), as long as it does not make the treatment less effective. If you are experiencing fatigue, talk to your doctor about whether taking a smaller dose is right for you.

There are a number of other tips for reducing fatigue:

  • Take several short naps or breaks during the day.

  • Take walks or do some light exercise, if possible.

  • Try easier or shorter versions of the activities you enjoy.

  • Ask your family or friends to help you with tasks you find difficult or tiring.

There are also prescription medications that may help, such as modafinil. Your health care team can provide guidance on whether medication is the right approach for your individual circumstances.

As you manage your cancer, it’s important to remember that you are a consumer of health care. The best way to make decisions about health care is to educate yourself about your diagnosis and get to know the members of your health care team, including doctors, nurses, nurse practitioners, physician assistants, dietitians, social workers and patient navigators.

Here are some tips for improving communication with your health care team:

Start a health care journal. Having a health care journal or notebook will allow you to keep all of your health information in one place. You may want to write down the names and contact information of the members of your health care team, as well as any questions for your doctor.

Prepare a list of questions. Before your next medical appointment, write down your questions and concerns. Because your doctor may have limited time, ask your most important questions first and be as specific as possible.

Bring someone with you to your appointments. Even if you have a journal and a prepared list of questions or concerns, it’s always helpful to have support when you go to your appointments. The person you bring may also think of questions to ask your doctor or remember details about your symptoms or treatment that you may have forgotten.

Write down your doctor’s answers. Taking notes will help you remember your doctor’s responses, advice and instructions. You can also ask the person who accompanies you to take notes for you, either in your journal or on a tablet or smartphone.

Record your visit if your doctor allows it. Recording the conversation with your doctor gives you a chance to hear specific information again or share it with family members or friends.

Incorporate other health care professionals into your team. Your medical oncologist is an essential member of your health care team, but there are other health care professionals who can help you manage your diagnosis and treatment:

  • Your primary care physician should be kept updated about your cancer treatment and any test results.
  • Your local pharmacist is a great source of knowledge about the medications you are taking. Have all of your prescriptions filled at the same pharmacy to avoid the possibility of harmful drug interactions.
  • Make sure your oncologist knows of any other medical conditions you have or any pain you are experiencing so that they can consult with your primary care physician or specialist as needed.

Remember, there is no such thing as over-communication.

Q: Can you explain the “ABCDEs” of melanoma and why they are important?A: A change in the appearance of a mole, described in words beginning with A, B, C, D and E, may be the first sign of melanoma. Consult with your doctor if you have any moles with the following features. There is a high likelihood of a successful outcome if the melanoma is recognized and treated at an early stage.

  • Asymmetrical: One side of the mole looks different from the other
  • Border: Irregular or vaguely defined borders
  • Color: Uneven coloring or multiple colors
  • Diameter: Larger than a pencil eraser or growing in size
  • Evolution: Growing or changing in any way

Q: Are melanomas genetic (inherited)?

A: Most melanomas occur in people where no family or genetic link can be found. However, there may be rare cases, not related to sun exposure, that have a genetic predisposition. For melanomas related to sun exposure, having a close relative with melanoma is a risk factor, but it’s not clear if the link is genetic or behavioral. Annual skin screenings for melanoma are recommended if you have a close relative with melanoma.

Q: I was treated with immunotherapy for my melanoma, and it has now recurred. Can I be treated with another immunotherapy?

A: More than likely, yes. Different types of immunotherapy work in different ways. It may even be that in some cases the immunotherapy you were treated with initially may be effective in treating the recurrence of the melanoma. This area is the subject of ongoing research.

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This booklet was made possible by Bristol Myers Squibb and an independent educational grant from Merck & Co. Inc.

Last updated May 09, 2020

The information presented in this publication is provided for your general information only. It is not intended as medical advice and should not be relied upon as a substitute for consultations with qualified health professionals who are aware of your specific situation. We encourage you to take information and questions back to your individual health care provider as a way of creating a dialogue and partnership about your cancer and your treatment.

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