Treating Advanced Skin Cancer

285 TreatingAdvSkinCancerBy Eleanor Mayfield

By one estimate, over the past three decades more people in the United States have had skin cancer than all other cancers combined.1 According to the American Cancer Society, 3.5 million cases of basal and squamous cell skin cancer are diagnosed each year.2 Rates of melanoma—the deadliest form of skin cancer—are on the rise,2 particularly among people younger than 40, increasing fourfold among men and eightfold among women in this age group since 1970.3

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.”

Advanced Melanoma

Since 2011 the US Food and Drug Administration (FDA) has approved four new drugs to treat advanced melanoma.

Yervoy® (ipilimumab) targets a protein that prevents the body’s immune system from recognizing and killing melanoma cells. It is the first drug shown to extend the lives of patients with advanced melanoma. In the trial that led to the approval of Yervoy in 2011, the drug added about four months to life on average.4 When researchers combined data from multiple studies of Yervoy, average survival was about 11 months, and some patients were still alive after seven years.5 The most common side effects included diarrhea, itching, skin rash, and colitis (inflammation of the lining of the colon).

Zelboraf® (vemurafenib) was the first to be approved in a new class of drugs known as BRAF inhibitors. It turns off a genetic mutation called BRAF V600, found in about half of patients with advanced melanoma, which allows melanoma cells to grow uncontrollably. Patients taking Zelboraf lived for nearly 16 months on average, compared with about six months for patients who took the drug dacarbazine.6 Nearly one in four patients treated with Zelboraf developed squamous cell cancer, a type of nonmelanoma skin cancer. Other common side effects included joint pain, skin rash, hair loss, and sun sensitivity.

Tafinlar® (dabrafenib) also targets the BRAF V600 mutation. Tumor growth was delayed by about five months in patients taking Tafinlar, compared with two to three months for patients taking dacarbazine.7 Serious side effects included new skin cancers (both squamous cell and melanoma), high fever, high blood glucose, and eye inflammation. Other, more common side effects included headache, joint pain, hair loss, and redness, swelling, and pain in the hands and the feet.

Mekinist® (trametinib) is a BRAF inhibitor that targets the BRAF mutation in a different way than Zelboraf or Tafinlar does. Tumor growth was delayed for about five months in patients taking Mekinist, compared with about six weeks for patients taking either dacarbazine or another chemotherapy drug, Taxol® (paclitaxel).8 Serious side effects included heart disease, lung diseases, and skin and eye complications. Other, more common side effects included rash, diarrhea, and swelling in the arms or legs.

As promising as all of these new drugs are, says Dr. Rigel, they often stop working within six months to a year as melanoma cells find another pathway that lets them start growing again. Researchers are now testing combinations of two or more of these new drugs, which they believe may produce better results than any one drug by itself. For example, in patients treated with a high dose of Mekinist plus Tafinlar, tumors stopped growing for more than nine months on average, compared with just under six months for patients who took Tafinlar alone. Nearly eight in 10 patients who received the combined regimen were still alive after one year.9

A drug called talimogene laherparepvec (TVEC) that is not yet FDA approved is showing promise in clinical studies. Patients treated with TVEC survived for nearly two years on average, compared with 19 months for patients who received an immune-system-stimulating drug.10 TVEC is a virus modified to grow inside tumor cells.

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.11 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.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.


The Truth about Tanning

New Jersey native Lauren Beloff grew up spending summer vacations at the shore, lying in the sun for hours every day, coating her skin with baby oil to promote tanning. In college she won a contest that offered a free month of indoor tanning, tried it, and was hooked.

“I would go two or three times a week,” she says. “They told me it was safer than going out in the sun, and I believed them. I loved hearing people say how great my tan looked.”

Then, in the summer of 2006, when she was 25, she noticed a “weird-looking” blemish on the right side of her chest. She went to a dermatologist, who diagnosed the spot as an early-stage melanoma.

Lauren is not alone. Among white women ages 15 to 39 in the United States, annual diagnoses of melanoma increased by 50 percent between 1980 and 2004.15 Moreover, indoor tanning before age 35 increases melanoma risk by 75 percent, according to a large international study.16

“Melanoma rates are rising four to five times more rapidly in young women than in young men,” says Dr. Rigel. “The one thing young women do differently than young men is they are about seven times as likely to go to a tanning salon.”

There is no such thing as a “safe” tan, says Dr. Rigel. “You tan because your body senses it’s being injured by ultraviolet radiation, and it produces melanin—the pigment in the tan—to protect itself. UV radiation from a tanning bed is 10 to 15 times more powerful than from natural sunlight, so of course you tan faster—but you are damaging your body 10 to 15 times more quickly.”

A week after her melanoma surgery, Lauren canceled her tanning salon membership. Now 32, she sees her dermatologist every six months and never lays out in the sun without wearing sunglasses and a hat and reapplying an SPF 50+ sunscreen every couple of hours. In 2013 she underwent Mohs micrographic surgery to remove a basal cell skin cancer from her face.

To other young women who covet the “glamorous” look of a tan, her message is: “the damage to your body and the scarring that will never go away should not make anyone want to tan.”


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.


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.


Resources

Skin Cancer

  • American Academy of Dermatology, aad.org/for-the-public or (866) 503-SKIN [7546]
  • Skin Cancer Foundation, skincancer.org or (212) 725-5176
  • National Cancer Institute,
    cancer.gov or (800) 4-CANCER [800-422-6237]
  • What You Need to Know About Melanoma and Other Skin Cancers, cancer.gov/cancertopics/wyntk/skin 

Skin Cancer Prevention

  • cancer.gov/cancertopics/pdq/prevention/skin/Patient
  • American Cancer Society: Lymphoma of the Skin, cancer.org/cancer/lymphomaoftheskin/index or (800) 227-2345

Cutaneous Lymphoma

  • Cutaneous Lymphoma Foundation, clfoundation.org or (248) 644-9014
  • Lymphoma Research Foundation, lymphoma.org or (800) 500-9976

References

1. 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.2010.4.

2. Cancer Facts & Figures 2013. American Cancer Society website. Available at: http://www.cancer.org/acs/groups/content/@epidemiologysurveilance/documents/document/acspc-036845.pdf. Accessed January 17, 2014.

3. Reed KB, Brewer JD, Lohse CM, Bringe KE, Pruitt CN, Gibson LE. Increasing incidence of melanoma among young adults: an epidemiological study in Olmsted County, Minnesota. Mayo Clinic Proceedings. 2012;87(4):328-34. doi: 10.1016/j.mayocp.2012.01.010.

4. 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.

5. 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.

6. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. New England Journal of Medicine2011;364(26):2507-16. doi: 10.1056/NEJMoa1103782.

7. 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.

8. Flaherty KT, Robert C, Hersey P, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. New England Journal of Medicine2012;367(2):107-14. doi: 10.1056/NEJMoa1203421.

9. 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.

10. 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 http://www.prnewswire.com/news-releases/amgen-presents-interim-overall-survival-data-from-phase-3-study-of-talimogene-laherparepvec-in-patients-with-metastatic-melanoma-232394381.html. Accessed January 17, 2014.

11. Sekulic A, Migden MR, Oro AE, et al. Efficacy and safety of vismodegib in advanced basal-cell carcinoma. New England Journal of Medicine2012;366(23):2171-79. doi: 10.1056/NEJMoa1113713.

12. 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.

13. 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.

14. 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.

15. 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.

16. 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.