by Diana Price Medically Reviewed by Dr. C.H. Weaver M.D. 5/2019
By one estimate, over the past three decades more people in the United States have had skin cancer than all other cancers combined. According to the American Cancer Society, 3.5 million cases of basal and squamous cell skin cancer are diagnosed each year. Rates of melanoma—the deadliest form of skin cancer—are on the rise, particularly among people younger than 40, increasing fourfold among men and eightfold among women in this age group since 1970.(1,2,3)
Most skin cancers, including melanoma, are highly curable with surgery if detected and treated early. For patients in whom skin cancer has progressed, however, treatment options have been limited. Several new drugs—the first generation of “targeted therapies” for advanced skin cancer—are starting to change that.
Unlike conventional chemotherapy drugs that attack both normal and cancerous cells, targeted therapies are designed to block specific substances or pathways in cancer cells that enable tumors to grow.
“Think of a light switch that’s stuck in the on position,” explains Darrell Rigel, MD, clinical professor of dermatology at New York University Langone Medical Center and a spokesman for the Skin Cancer Foundation. “As long as the switch is on, the cancer keeps growing. What these new drugs do is cut the wire or turn the switch off.”
Although none of these new drugs is a cure, Dr. Rigel emphasizes, “they are much, much better than anything we have had before to treat advanced skin cancer.”
Britta Fortson was 18 years old when she was diagnosed with ocular melanoma (cancer of the eye), but she responded well to treatment and went to college a few months later as planned. During the following two decades, she started running marathons, became a speech pathologist, got married, and had two children. Then, in the spring of 2015, her primary care doctor noticed elevated liver enzymes on one of her routine blood tests. Further testing revealed that the melanoma had returned and had metastasized to her liver.
“I was devastated,” says Britta, now 43, of Jacksonville, Florida. “When I started reading studies online, it looked like most people with Stage IV melanoma lived for about six months. I couldn’t function and started planning for my demise.”
Britta’s sister began researching treatment options, and she urged Britta to see a doctor at MD Anderson Cancer Center in Houston who specialized in immunotherapy—medications that stimulate the immune system to recognize and destroy cancer cells.
“In the past few years, we’ve seen a real revolution in our therapies for late-stage melanoma,” says Sapna Patel, MD, Britta’s physician in the Department of Medical Melanoma Oncology at MD Anderson. “We’ve been aware of drugs that can activate the immune system, but in the past they were used for rare cases and had serious side effects. The new treatments are benefiting a larger population and have more reasonable side effects.”
Britta was accepted into a clinical trial and started taking a combination of two immunotherapy drugs. About 60 percent of patients typically respond to this treatment, says Dr. Patel, and Britta anxiously waited to see if she would be in that group.(1) She flew to Houston every three weeks for infusions of the medications, and after three months CT (computed tomography) scans revealed good news: two of the tumors were almost gone and two were smaller. Britta continues to take the medication and appears to have no cancer in her body.
Outsmarting Cancer Cells
Shailender Bhatia, MD, an associate professor of medicine in the Division of Medical Oncology at the University of Washington School of Medicine in Seattle, has been studying innovative melanoma treatments for more than a decade. “For years researchers were trying new things that kept failing,” Dr. Bhatia says. “But we’ve made tremendous progress recently, and in the past five years more than 10 new treatments have been approved by the US Food and Drug Administration.” These new medications were initially only used individuals with advanced disease but clinical studies have shown they can be used to effectively treat earlier stage melanomas and improve survival after surgery.
Immune checkpoint inhibitors Cancer cells proliferate by hiding from the body’s immune system, and these medications help the immune system recognize cancer cells as invaders. In many cases, patients start on what is known as a PD-1 inhibitor, says Dr. Bhatia: “Cancer cells have different methods of hiding from the immune system, and one strategy is pushing a brake on immune cells so they slow down. PD-1 inhibitors essentially prevent the cancer cells from seeing the brake on the immune cells, which allows the immune system to stay active and do its function.”
Managing Side Effects
Because ocular melanoma can be particularly aggressive, Britta started immediately on a checkpoint inhibitor combination known as Opdivo® (nivolumab) and Yervoy® (ipilimumab). Within a few weeks, she was experiencing diarrhea, lung inflammation, fatigue, and arthritis in her knees, hands, and feet. Her doctor prescribed an inhaler to treat the chest pain and coughing and an anti-inflammatory drug for the arthritis.
“Even though I had to stop working due to the side effects, I feel like my symptoms are under control,” says Britta. “I try to go running early in the morning because the joint pain increases throughout the day, and I usually have to take a nap due to the fatigue.”
Britta does not know whether she will continue taking the immunotherapy drugs after the clinical trial, but some patients with Stage IV melanoma stay in remission even after discontinuing medication. This occurs when the immune system starts replicating the drug’s mechanism independently.
“This is really the goal of immunotherapy,” Dr. Patel explains. “When we get a flu shot, we are immunized for the year, and in melanoma there should be a handoff from the drugs to your own immune system. We are not sure when that handoff occurs and why it happens in some people and not others.”
Former president Jimmy Carter, whose melanoma spread to his brain and lungs, was prescribed a checkpoint inhibitor known as Keytruda® (pembrolizumab) for six months in 2015, and he has remained cancer-free even after discontinuing the medication.
Targeted Therapy With Precision Cancer Medicines
While immunotherapy empowers the immune system, researchers have also recently pioneered new chemotherapy treatments that target melanoma cells directly. Traditional chemotherapy drugs kill all cells that grow rapidly, which can lead to nausea, hair loss, sores in the mouth, low white blood cells counts, and other symptoms.
Chemotherapy drugs can specifically target melanoma tumors that have what is known as a BRAF gene, which occurs in about 50 percent of individuals diagnosed with melanoma.(3) This mutation leads to a hyperactive protein that causes melanoma cells to multiply rapidly, and the new treatments bind to this mutation and prevent it from growing. Something known as MEK proteins work together with the BRAF proteins, and the FDA has also approved new drugs that target the MEK proteins.
These targeted therapies have far fewer side effects than traditional chemotherapy, but they are typically effective for only about a year because the cancer cells usually find a way to avoid the drug mechanism, says Dr. Buchbinder. “We usually use these drugs for extending life rather than eliminating cancer,” she explains. “If a patient is in a lot of discomfort and needs a quick response, these medications can be used in combination.”
The Next Frontier
The innovative treatments approved in the past several years are saving lives, but for now only a little more than half of patients are responding to these medications. Dr. Bhatia predicts that the next wave of research will explore the following:
- Using immunotherapy drugs in combinations
- Using immunotherapy treatment on patients with Stage III melanoma—cancer that has spread to the lymph nodes
- Using immunotherapy drugs in combinations with targeted gene therapy
- Imlygic (Talimogene laherparepvec TVEC) is a genetically modified live oncolytic herpes virus therapy. In essence, Imlygic consists of a herpes virus that has been genetically modified through laboratory processes. Imlygic is injected into the site of the cancer where the modified herpes virus replicates inside cancer cells and causes the cancer cells to rupture and die.(10)
“The most remarkable thing is watching these patients live longer while enjoying an excellent quality of life,” says Dr. Bhatia. “While we do not know definitively if they are cured, many are in complete remission and just come in for surveillance scans. We have the happy problem of dealing with an increased volume of survivors in our clinic mostly receiving maintenance treatment.”
Advanced Basal Cell Cancer
Advanced basal cell cancer is a rare disease for which there was no effective treatment until the approval of Erivedge® (vismodegib) in 2012. The drug blocks cellular signals that tell the cancer cells to grow. Tumors stopped growing for 9.5 months on average. After a further two years of follow-up, patients with metastatic basal cell cancer (tumors had spread to other organs) had lived for just under three years on average.(11,12)
A few patients have been taking the drug for as long as five years, says Aleksandar Sekulic, MD, PhD, assistant professor of dermatology at the Mayo Clinic in Scottsdale, Arizona, who led the trial that resulted in the approval of Erivedge. The most common side effects of treatment have included hair loss, muscle cramps, and the loss of taste sensation. _
New Treatments for Advanced Skin Lymphoma
The rash on Judy Jones’s neck was “about the size of a baseball,” itchy, and wouldn’t go away no matter how many creams and ointments her dermatologist prescribed for it.
After about a year of trying various treatments that proved ineffective, Judy found a new rash on her abdomen. It was then her doctor referred her to a specialist at the University of Michigan Medical Center in Ann Arbor, about 25 miles from her home in the Detroit area.
The specialist quickly recognized the rash as an early-stage cutaneous lymphoma, a rare cancer of white blood cells that occurs in the skin.
Judy’s experience—undergoing months of ineffective treatment before getting an accurate diagnosis—is common for patients with cutaneous lymphoma, says Lauren Pinter-Brown, MD, a hematologist-oncologist and clinical professor of medicine at the University of California, Los Angeles, Jonsson Comprehensive Cancer Center.
“Many patients have had a rash for a long time and have usually been told it is psoriasis or eczema,” she says. “Patients will say to me, ‘I’ve had this rash for years, and now I find out it’s a lymphoma?’”
Cutaneous lymphoma is usually very slow growing, and many patients can manage it successfully for many years, says Dr. Pinter-Brown. Judy Jones is one of those patients: Since the diagnosis in 1990, she has had treatment several times for recurrences. The cancer has now been in remission since 2008.
Although cutaneous lymphoma occurs in the skin, it is not a primary skin cancer like basal cell cancer or melanoma. A key difference is that although doctors strongly advise patients with melanoma and other primary skin cancers to protect themselves against the sun’s ultraviolet (UV) rays, those same rays—sometimes in combination with drugs that increase sensitivity to sunlight—can be a treatment option for patients with cutaneous lymphoma.
For about one in three patients with cutaneous lymphoma, the disease can progress or start growing faster. A skin rash covering most of the body, tumors that appear as red bumps on the skin, and evidence of cancer in lymph nodes—all are signs that the disease is progressing.
Two novel drugs, Zolinza® (vorinostat) and Istodax® (romidepsin) have been approved to treat cutaneous lymphoma that has progressed or stopped responding to other treatments. Both drugs “encourage” cancer cells to die or stop growing by interfering with DNA (the material that carries the genetic instructions for life).
Another drug, Folotyn® (pralatrexate), although not approved by the FDA to treat cutaneous lymphoma, has been shown to shrink tumors in patients with cutaneous lymphoma in whom cancer has come back after an average of four previous chemotherapy treatments.13
Most patients achieve a partial remission with these drugs, says Dr. Pinter-Brown. Common side effects of Zolinza and Istodax include fatigue and loss of appetite. Nausea, mouth sores, and low blood cell counts are among the most common side effects of Folotyn.
Sunscreen and Skin Cancer: New Evidence
Although sunscreen has long been recommended to prevent sunburn, whether it also prevented skin cancer, especially melanoma, was not clear. A recent study in Australia showed for the first time that regular use of a broad-spectrum sunscreen can reduce the number of new cases of melanoma.
One group of white Australian adults ages 20 to 69 received free, unlimited supplies of a broad-spectrum SPF 16 sunscreen; they were carefully trained in how to apply it and were asked to use it daily as instructed for five years. A second, comparison group was asked to continue using, or not using, sunscreen as they always had. After 15 years of follow-up, twice as many people in the comparison group (22) had been diagnosed with melanoma as in the sunscreen group (11).14
“Although relatively small, this is the first well-designed study to show a reduction in melanoma with daily use of a broad-spectrum sunscreen,” says Dr. Rigel.
New Rules for Sunscreen
Major changes have taken place in the sunscreen aisle thanks to new, stricter FDA regulations. You will no longer see products labeled “sunblock” or claiming to be “sweatproof.” And products can be labeled “broad spectrum”—meaning they protect against both ultraviolet B (UVB) radiation from the sun, which causes sunburn, and ultraviolet A (UVA) radiation, which causes skin aging and other
damage—only if they have passed an FDA test.
Here are some other changes:
Those sunscreens labeled SPF 70 or higher? Gone. The highest SPF number you will now see is 50+. The FDA decided that the highest SPF numbers were misleading because those products blocked barely any more UV rays than those with lower numbers.
Sunscreens with an SPF of 15 or lower now carry a warning that they protect against sunburn but not skin cancer or premature skin aging.
No sunscreen can be labeled “waterproof”—only “water resistant” for either 40 or 80 minutes.
Like over-the-counter medications, sunscreens now carry labels that list active ingredients, directions for use, and warnings about any possible dangers or interactions.
- Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. New England Journal of Medicine. 2015;373(13):23-34. doi: 10.1056/NEJMoa1504030.
- Key statistics for melanoma skin cancer. American Cancer Society website. Available at: . Accessed January 9, 2017.
- Targeted therapy for melanoma skin cancer. American Cancer Society website. Available at: . Accessed January 9, 2017.
- Stern, RS. Prevalence of a history of skin cancer in 2007: results of an incidence-based model. Archives of Dermatology. 2010;146(3):279-82. doi: 10.1001/archdermatol.2010.
- Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. New England Journal of Medicine. 2011;364(26):2517-26. doi: 10.1056/NEJMoa1104621.
- Schadendorf D, Hodi FS, Robert C, et al. Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in metastatic or locally advanced, unresectable melanoma. Paper presented at: 38th Congress of the European Society for Medical Oncology; September 27–October 1, 2013; Amsterdam, Netherlands. Abstract LBA24.
- Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. New England Journal of Medicine. 2011;364(26):2507-16. doi: 10.1056/NEJMoa1103782.
- Hauschild A, Grob JJ, Demidov LV, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2012;380(9839):358-65. doi: 10.1016/S0140-6736(12)60868-X.
- Flaherty KT, Robert C, Hersey P, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. New England Journal of Medicine. 2012;367(2):107-14. doi: 10.1056/NEJMoa1203421.
- Flaherty KT, Infante JR, Daud A, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. New England Journal of Medicine. 2012;367(18):1694-703. doi: 10.1056/NEJMoa1210093.
- Amgen Presents Interim Overall Survival Data from Phase 3 Study of Talimogene Laherparepvec in Patients with Metastatic Melanoma [news release]. November 18, 2013. Available at . Accessed January 17, 2014.
- Sekulic A, Migden MR, Oro AE, et al. Efficacy and safety of vismodegib in advanced basal-cell carcinoma. New England Journal of Medicine. 2012;366(23):2171-79. doi: 10.1056/NEJMoa1113713.
- Sekulic A, Migden MR, Oro AE, et al. Long-term safety and efficacy of vismodegib in patients with advanced basal cell carcinoma (aBCC): 24-month update of the pivotal ERIVANCE BCC study. Paper presented at: European Academy of Dermatology and Venereology; October 3, 2013; Istanbul, Turkey. Abstract FCO2.7.
- Horwitz SM, Kim YH, Foss F, et al. Identification of an active, well-tolerated dose of pralatrexate in patients with relapsed or refractory cutaneous T-cell lymphoma. Blood. 2012;119(18):4115-22. doi: 10.1182/blood-2011-11-390211.
- Green AC, Williams GM, Logan V, Strutton GM. Reduced melanoma after regular sunscreen use: randomized trial follow-up. Journal of Clinical Oncology. 2011;29(3):257-63. doi: 10.1200/JCO.2010.28.7078.
- Purdue MP, Freeman LE, Anderson WF, Tucker MA. Recent trends in incidence of cutaneous melanoma among US Caucasian young adults. Journal of Investigative Dermatology. 2008;128(12):2905-8. doi: 10.1038/jid.2008.159.
- International Agency for Research on Cancer Working Group on artificial ultraviolet (UV) light and skin cancer. The association of use of sunbeds with cutaneous malignant melanoma and other skin cancers: a systematic review. International Journal of Cancer. 2007;120(5):1116-22. doi: 10.1002/ijc.22453.
- Chapman PB, Hauschild A, Robert C, et al. Phase III randomized, open-label, multicenter trial (BRIM3) comparing BRAF inhibitor vemurafenib with dacarbazine (DTIC) in patients with V600E BRAF-mutated melanoma. Paper presented at: 47th Annual Meeting of the American Society of Clinical Oncology; June 3-7, 2011; Chicago, IL. Abstract LBA4.
- Wolchok JD, Thomas L, Bondarenko IN, et al. Phase 3 randomized study of ipilimumab (IPI) plus dacarbazine (DTIC) vs. DTIC alone as first line treatment in patients with unresectable Stage III or IV melanoma. Paper presented at: 47th Annual Meeting of the American Society of Clinical Oncology; June 3-7, 2011; Chicago, IL. Abstract LBA5.
- O’Day S, Hodi FS, McDermott DF, et al. A phase III, randomized, double-blind, multicenter study comparing monotherapy with ipilimumab or gp100 peptide vaccine and the combination in patients with previously treated, unresectable Stage III or IV melanoma. Paper presented at: 46th Annual Meeting of the American Society of Clinical Oncology; June 4-8, 2010; Chicago, IL. Abstract 4.