Thanks to clinical trials, people with advanced skin cancers have more treatment options

Skin cancer is the most common cancer in the United States. Basal cell carcinoma (BCC) is the most common type of skin cancer, followed by squamous cell carcinoma (SCC) and melanoma. In this e-booklet, we’ll discuss the standard and new treatment approaches to advanced, or metastatic, skin cancers—those that have spread from their original location on the skin to other parts of the body. We’ll also discuss how to manage treatment-related side effects and the best ways to care for your skin during treatment.

Basal and Squamous Cell Carcinomas

Most basal and squamous cell carcinomas are removed with simple procedures done in a doctor’s office or by surgery or, less commonly, treated with radiation. If a tumor is too large or penetrates too deeply into the skin and cannot be treated with surgery or radiation, doctors use medications to destroy the cancer.

Several years ago, researchers discovered that more than 70 percent of all BCCs have certain gene mutations, or changes, that lead to tumor growth. These changes occur in the “Hedgehog pathway.” (A pathway is a series of actions among molecules in cells, including cancer cells, that can lead to growth, for example.) Finding the mutations meant that drugs could be designed to target those pathways.

Vismodegib (Erivedge) is one such targeted treatment. It was made to target the specific cell mechanisms that are important for the growth and survival of tumor cells. (Targeted treatments are designed to spare healthy tissues and tend to cause less severe side effects than chemotherapy.)

Vismodegib is a capsule taken by mouth once a day. It is the first drug approved by the U.S. Food and Drug Administration (FDA) for adults with BCC that has spread to other parts of the body, comes back after surgery, or cannot be treated with surgery or radiation. In the largest study so far of vismodegib in advanced BCC, the tumors shrank in most people. In a few patients, the tumors disappeared for a period of time. New studies are underway to see how vismodegib can be used before or after surgery, so doctors could do smaller operations and patients could heal faster.

Melanoma

Most cases of melanoma are diagnosed at an early stage, with the tumor—often a single, thin spot, or lesion—located on the skin. But even after surgery to remove melanoma, the cancer can come back and spread. When melanoma does spread, or metastasize, surgery and radiation are less effective. Until recently, few medications were available to treat advanced melanoma.

But in the past few years, four drugs have been approved by the FDA, and others are likely to be approved soon. The treatments work either by helping the immune system destroy melanoma cells (immunotherapy) or blocking their ability to grow, divide and spread (targeted treatments).

Immunotherapies

Aldesleukin (interleukin-2, Proleukin). Since the late 1990s, aldesleukin has been approved as a standard treatment for metastatic melanoma. It is given through a vein. Aldesleukin helps the body’s immune system shrink and destroy tumors more effectively. The drug benefits some people who receive it. But aldesleukin is not used as commonly today because there are newer options with fewer side effects.

Ipilimumab (Yervoy). This drug, also given through a vein, helps the immune system in a different way from aldesleukin. Ipilimumab seeks out and locks onto CTLA 4, a protein that normally helps keep immune system cells (called T cells) in check. By blocking the action of CTLA-4, ipilimumab is thought to help the immune system destroy melanoma cells. The first such medication approved for treating people with melanoma, ipilimumab helps people with metastatic melanoma survive longer. It is given once every three weeks, for a total of four doses. This medication does not start working right away. It can take from one to four months before ipilimumab begins to work.

Targeted Treatments

About one-half of all melanomas have a gene mutation called BRAF that leads to tumor growth. For these melanomas, three targeted treatments have been approved by the FDA:

Vemurafenib (Zelboraf).Many patients who take vemurafenib survive longer; their tumors shrink within a matter of weeks and take longer to begin growing again. Vemurafenib, a tablet taken by mouth, can shrink tumors in areas of the body such as the liver, bowel and bone that are difficult to treat with chemotherapy or surgery.

Dabrafenib (Tafinlar) and trametinib (Mekinist). These drugs, taken by mouth as tablets, block the same growth pathway as vemurafenib. Dabrafenib targets the BRAF protein, whereas trametinib blocks another protein called MEK, which is “switched on” by BRAF. Although their combined use has not been approved by the FDA, dabrafenib and trametinib given at the same time may be more effective than either one by itself because each one focuses on a different part of cancer cell growth.

Clinical trials, and the patients who take part in them, are advancing our knowledge about how best to treat advanced skin cancers. In this section, we discuss some of the most important medications researchers are studying now.

Basal Cell Carcinomas

Vismodegib. People with a rare disease that is present at birth called basal cell nevus syndrome can have up to hundreds of basal cell skin cancers. In clinical trials, nearly all the tumors disappeared after patients with this syndrome took vismodegib for several months. That is important news because surgery and radiation are not possible in many of these cases. But most people with this type of BCC can benefit from surgery. In a small clinical trial, 10 such patients were given vismodegib before surgery. Their tumors\ shrank, and they healed faster.

Squamous Cell Carcinomas

Cetuximab (Erbitux). The FDA has already approved this targeted treatment for certain types of colorectal and head and neck cancers. Clinical trials now show that cetuximab given through a vein is also effective in treating advanced squamous cell carcinomas. This drug works by blocking tumor cells’ growth signals, which destroys the cancer. Doctors are already prescribing cetuximab to some patients with SCCs that cannot be treated with surgery or chemotherapy.

Melanoma

Earlier, we mentioned the common gene mutation BRAF, which leads to melanoma growth, and three drugs that block it (vemurafenib, dabrafenib and trametinib). There are also other mutations that may lead to melanoma growth, and researchers are learning how best to block them.

Imatinib (Gleevec) and sunitinib (Sutent). About 3 percent of melanomas have mutations in the KIT receptor, which is found on some healthy cells as well as tumor cells. (A receptor is a molecule on the surface of a cell. Receptors are switched on when a specific substance attaches to them, causing an action in the cell.) When switched on normally, KIT receptors tell the cell to grow when it is needed. But in some types of melanoma, the KIT receptors are always switched on, making the cell grow uncontrollably into cancer. Clinical trials are showing that imatinib and sunitinib (both of which are FDA-approved to treat other cancers and are given by mouth) can block the mutated KIT receptor. With these drugs, melanoma tumors with the KIT mutation shrink and can be controlled for longer periods of time.

Nivolumab. Like ipilimumab, which has controlled advanced melanoma for a long time in some patients, nivolumab activates the immune system. It is a medicine given through a vein that blocks a protein called PD-1, a tumor-cell defense mechanism.

Two recent clinical trials have shown encouraging results with nivolumab in treating people with advanced melanoma. In one study, almost half of the patients who received nivolumab survived for at least two years. This drug starts to shrink tumors in most patients within weeks, which may be faster than ipilimumab. Also, compared to ipilimumab, the side effects of nivolumab are often milder and less frequent. Nivolumab may soon be approved for advanced melanoma.

Because nivolumab and ipilimumab work in different ways to help the immune system, researchers are combining them in clinical trials now underway. Early results are encouraging. In the future, nivolumab and ipilimumab may be prescribed together to better destroy melanoma cells.

Lambrolizumab. Like nivolumab, lambrolizumab is a medicine given through a vein that blocks PD-1. Early clinical studies show encouraging results with lambrolizumab in treating people with advanced melanoma. For patients whose cancer grew after taking ipilimumab, nearly half had tumors that shrank with lambrolizumab. Researchers continue to study how people can benefit most from this treatment.

MPDL3280A. This medication does not have a name yet because it is in an earlier stage of development than other drugs described here. MPDL3280A is designed to help the immune system destroy melanoma cells by targeting the PD-L1 protein. In one clinical trial, people with metastatic melanoma received injections of this drug. In some patients, the tumors shrank within days of receiving the injections. Six months after treatment, the tumor had not continued to grow in nearly half of the patients. This treatment may work better in people whose tumors have the PD-L1 protein, but it has also benefitted some people who did not have the PD-L1 protein.

Selumetinib. This pill, taken by mouth, blocks the tumor growth signal MEK. Selumetinib appears to be a promising treatment for people who have advanced uveal melanoma, melanoma that starts in the eye. This is the first time that a drug has been shown to improve outcomes for people with this diagnosis. Early results show that selumetinib shrank the eye tumors in half of those who received it. It also took longer for the tumor to continue growing with selumetinib than with the standard treatment temozolomide (Temodar and others).

As with all cancer treatments, immunotherapies and targeted 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. Doing so will improve your quality of life and allow you to stick with your treatment plan.

Rash. Many people who take immunotherapies or targeted treatments such as cetuximab, vemurafenib or ipilimumab get an itchy rash on their face and upper body and sometimes the scalp. With cetuximab, it may look like acne and may cause pain. For the acne-like rash, your doctor may prescribe oral antibiotics and corticosteroid creams. With ipilimumab and vemurafenib, the rash is red, flat and itchy and usually affects the trunk (the main part of the body, not including the head or limbs). Topical or oral corticosteroids are usually needed to treat the measles-like rash that results from ipilumumab and vemurafenib. These rashes usually occur within the first month of treatment. Once rash is treated and has improved, it does not come back as severely. Avoid scratching a rash, as it can lead to infection. Ask your doctor about using over-the-counter medications that can help. In general, prescription medications are more effective.

Sensitivity to sunlight. Some drugs, such as vemurafenib, can increase the risk of getting sunburned. It’s always a good idea to reduce your exposure to sunlight, if you are unprotected by sunscreen. You can get sunburned even through the glass in your car or home, so it’s important to always use sunscreen, especially between 10 a.m. and 4 p.m. See sidebar for tips on sunscreen use.

Spots on the skin. Some people taking vemurafenib and dabrafenib may develop red or pink skin bumps. These bumps, a type of early-stage squamous cell skin cancer, can appear suddenly or start to grow quickly. Report them to your doctor right away so they can be examined and removed.

Inflammation around the fingernails and toenails. About 20 percent of people treated with cetuximab develop redness and swelling around the nail folds (where the nail meets the skin). This condition can be treated with topical antibiotics and, if needed, a small surgical procedure.

Dry skin. It’s important to use moisturizers to manage this side effect of skin-cancer treatment, because skin that is dry may allow too much water to be lost from the body, leading to intense itching. Dry skin and cracks that develop in the skin may allow bacteria or viruses to penetrate, causing infections. See sidebar for tips on the best way to use moisturizers.

Hair changes. Using vismodegib can lead to thinning hair. There are various ways to camouflage thin hair, including sprays, powders and over-the-counter minoxidil foam (Rogaine and others). Cetuximab, and other drugs in its class, can cause the hair to become very curly. Women may lose some hair on their scalp or develop hair growth on the face. Because the skin is made sensitive by anti-cancer medication, doctors discourage the use of chemical hair removal or waxing.

Change in taste. About half the people who take vismodegib develop a metallic or cardboard-like taste in their mouth. Your doctor or a registered dietitian can suggest a specific diet to help ease this side effect.

Muscle spasm. About 70 percent of people on vismodegib develop muscle spasm, which can be severe. Your doctor can prescribe anti-spasm or pain medications, if needed.

Changes in bowel habits. If you are taking ipilimumab, it’s very important to tell your doctor if you experience increased gassiness, bloating, diarrhea or other changes in bowel habits. He or she may prescribe medications for these symptoms and/or change your diet. These side effects should be treated early to avoid more serious problems, such as dehydration or damage to the intestines.

Hand-foot syndrome. Some patients taking treatments that target BRAF (such as vemurafenib or dabrafenib) develop tenderness or thickening of the palms and soles that look like calluses. If you experience these side effects, it’s important to use a moisturizer containing urea, ammonium lactate or salicylic acid. Try to avoid placing pressure or friction on your hands and feet by wearing well-padded socks and soft shoes and slippers made with memory foam or calfskin. A podiatrist can help remove thickened calluses or treat painful areas. If tenderness or inflammation become severe, talk to your doctor about using topical corticosteroid creams or pain medications such as patches containing lidocaine.

Q. Basal cell and squamous cell cancers run in my family. What measures can I take to prevent my young children from getting skin cancer?

A. The number one recommendation is to avoid excess sun exposure. Getting a suntan or sunburn increases the risk of developing basal cell or squamous cell cancer, as well as melanoma. Make sure your children are protected with broad-spectrum sunscreens (reapplied every two hours), wide-brimmed hats, and sunglasses. As much as possible, they should seek shade during peak sun times between 10 a.m. and 4 p.m.

Q. What can I do to get ready for my skin cancer treatment? How do I prepare myself?

A. Maintaining a good “performance status”—the ability to carry out ordinary tasks and daily activities—is an important part of preparing for cancer treatment and the challenges you may face. Light exercise and healthy eating can help you cope better with your treatment. Ask your doctor to recommend a registered dietitian and an exercise specialist to help you come up with a plan that works for you.

It’s also important to include mental preparation. Talk to your doctor or nurse about what to expect. If you are feeling anxious or distressed and need support outside of your network of family and friends, work with an oncology social worker to address your concerns.

Q. My doctor referred me to a dermatologist for treatment of actinic keratoses. What are they, and can they lead to skin cancer?

A. These small, flaky pieces of skin look a little bit like a scab. They can appear on the forehead and other parts of the face, as well as the neck, hands, arms and chest— all areas exposed to the sun. You might be able to wash or rub them off, but they tend to come back in the same place. Actinic keratoses are common, and many cause no problem. However, some can develop into squamous cell cancer. If you have many actinic keratoses, you may be at a higher risk for not only squamous cell cancer but also basal cell cancer or even melanoma. The spots can be treated by a doctor with liquid nitrogen to remove the abnormal cells. Be sure to reduce your sun exposure and have yearly checkups.

Q. Can you explain what the “ABCDEs” of melanoma are and why they’re important?

A. If you have any moles with the following features, ask your doctor to check them out. Such changes in the appearance of a mole may be the first signs of melanoma. If recognized and treated early, this cancer is almost always cured or stopped from spreading.
• 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

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This booklet was made possible by Genentech, a Member of the Roche Group, and Celgene.

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.