THE MOST DEADLY SKIN CANCER
Clinical and translational research at Ohio State and elsewhere are improving care for people with melanoma, one of the few cancers that is increasing in incidence
BY BOB HECKER
Melanoma is the most lethal form of skin cancer, and its incidence has been on the rise for three decades or more in the United States, according to the American Cancer Society (ACS). And though it accounts for less than 5 percent of all skin-cancer cases, it is responsible for the vast majority of skin-cancer deaths. The ACS also notes that:
• An estimated 77,000 people will be diagnosed with melanoma in 2013, and nearly 9,500 will die of the disease;
• Caucasians have a 23-times greater lifetime risk than African-Americans for developing the disease;
• Melanoma incidence rates for Caucasians rose by almost 3 percent per year from 2005-2009.
Despite the upward trajectory and poor survival rates, Kari Kendra, MD, PhD, who leads the expanding melanoma program at Ohio State’s Comprehensive Cancer Center – James Cancer Hospital and Solove Research Institute (OSUCCC – James), says there is cause for optimism.
“The FDA has approved three drugs—vemurafenib, dabrafenib and ipilimumab—for melanoma treatment in the past two years,” says Kendra, a medical oncologist and researcher who chairs the Melanoma Disease-Specific Committee at the OSUCCC – James. “Before that, there hadn’t been a new one approved for about 20 years.”
Vemurafenib is approved for treating late-stage disease and targets the BRAF V600E gene mutations. BRAF mutations occur in about 60 percent of melanomas and signal a poor prognosis. Dabrafenib also targets BRAF mutations, and ipilimumab is a monoclonal antibody designed to boost immune responses to melanoma cells.
Kendra says these agents and others in development, including some by OSUCCC – James investigators, are offering more options for biologic therapies that enhance the body’s antitumor responses and for targeted therapies based on mutational analysis.
“If we can identify genetic mutations in tumors, we can apply a therapy that targets them,” she explains. “With newer therapies, we are seeing enhanced response rates, and we are working toward obtaining better survival rates.”
The comprehensive, multidisciplinary and research-based melanoma program at the OSUCCC – James provides patient care that involves innovative immunotherapies, targeted therapies with novel mechanisms of action, and programs that offer patient education and support.
“What sets us apart is the quality and number of our clinical trials, which make promising new drugs and treatment strategies available to patients,” Kendra says. “We also take innovative approaches to therapy and have an incredible support team for patients during treatment.”
“We have the support people necessary to handle melanoma cases and deal with any problems that may arise, and we hold interactive discussions in at least five multidisciplinary patient conferences per month,” adds Thomas Olencki, DO, a medical oncologist and researcher who specializes in cutaneous and ocular melanoma, and other skin cancers.
Patient volume for ocular melanoma at the OSUCCC – James has tripled in the past few years following the addition of ophthalmologist Colleen Cebulla, MD, who has clinical and research interests in ocular oncology, Olencki notes.
Surgical oncologist, clinical geneticist and researcher Doreen Agnese, MD, often provides the initial treatment after a melanoma diagnosis. “I assess cutaneous, subcutaneous and nodal masses and resect metastatic disease,” she says.
“Surgeons, medical oncologists, radiation oncologists and dermatologists work closely to provide coordinated care for our melanoma patients, including close surveillance of future skin lesions,” says Evan Wuthrick, MD, radiation oncologist and clinical researcher.
Wuthrick notes that radiation therapy is used to treat melanoma in: areas of the body where surgery would be difficult or risky; metastatic tumors in the brain and spine to improve quality of life; and lymph node chains after surgery in patients at high risk of recurrence in the nodes.
Why the Rising Incidence?
Risk factors for melanoma include a personal or family history of the disease, the presence of atypical or numerous moles (more than 50), and immune suppression. Added to that are environmental, social and dietary factors that might increase melanoma incidence, Olencki says. These include depletion of Earth’s ozone layer, widespread use of tanning devices, prolonged exposure to sunlight without proper protection, and nutrition low in fruits and vegetables, many of which have anticancer properties.
Tatiana Oberyszyn, PhD, a research pathologist who studies skin cancer at the OSUCCC – James, examines the effects of ultraviolet (UV) radiation in sunlight on the skin.
“UVB, which causes sunburn, was once believed to be the most important wavelength in the development of skin cancer, so initial sunscreens were designed to block UVB but not the longer wavelength, UVA, which penetrates deep into the skin,” Oberyszyn explains. “We now know that UVA exposure is also a factor, and most sunscreens today block both wavelengths.
“But there was a period when people used sunscreens that blocked only UVB and were actually exposing themselves to more UVA, which may translate to the increases we’ve seen in the past 30 years.”
Oberyszyn says indoor tanning beds and sun lamps are another big factor, particularly among women, pre-teens and teenagers, who are developing skin cancers at earlier ages. Kendra says she has treated melanoma patients as young as age 14.
In 2009, the International Agency for Research on Cancer (IARC), part of the World Health Organization, classified UV-emitting tanning devices that emit ultraviolet radiation as “carcinogenic to humans.” The IARC noted that, “Combined analysis of over 20 epidemiological studies shows that the risk of cutaneous melanoma is increased by 75 percent when the use of tanning devices starts before age 30.”
People also tend to wear fewer layers of clothing when outdoors in warm weather and mistakenly believe that the clothes they do wear protect them from UV exposure, Oberyszyn says. “And then there’s the past promotion by the media that people look better and healthier with a tan,” she adds.
Cutaneous Oncology Center
“The OSUCCC – James Cutaneous Oncology Center encompasses melanoma, non-melanoma skin cancers and rare tumors of the skin,” says Shannon Campbell Trotter, DO.
• The Pigmented Lesion Clinic, directed by Trotter, specializes in skin surveillance of those at risk for melanoma or with a history of the malignancy. The clinic offers full body photography, or mole mapping, to create a baseline for observing changes in existing moles or new lesions for earlier detection. Patients can take copies of the photos home for comparison when performing skin self-exams.
• The High Risk Clinic focuses on skin surveillance in high-risk populations, including organ transplant recipients and patients with chronic lymphocytic leukemia, HIV and genetic conditions like Lynch syndrome and basal cell nevus syndrome that predispose to skin cancer.
• The Rapid Access Clinic reserves daily appointments for quick evaluation of potential skin cancers. This is available for internal referrals as well as for community physicians who need expedient evaluation of a patient’s lesion.
Trotter says patient volume has expanded in the clinics, which are available four days a week. “We can communicate directly with other members of the patient’s care team and collaborate on clinial trials. We treat patients as individuals with a customized therapeutic plan that meets their needs,” she adds.
“Clinical trials are necessary to improve overall survival in melanoma patients and to improve their quality of life,” Kendra says. “It is only with these studies that we have a chance to find that durable response, that ‘cure.’”
The number of patients accrued to melanoma clinical trials at the OSUCCC – James increased 10-fold from 2005-10 and continues to rise, she says.
“We’ve maximized accruals by providing trials that meet our patients’ needs and by making community physicians aware of the trials we offer,” Kendra explains. “We currently have six trials open and seven pending, meaning they have been funded and will soon start accruing.
“Our goal is to keep increasing the number of National Cancer Institute (NCI)-funded trials and the number of trials initiated by OSUCCC – James investigators.”
Examples of Clinical Trials for Cutaneous Melanoma at the OSUCCC–James
ECOG-E1609 – A national phase III trial comparing ipilimumab with
high-dose interferon alfa-2b in patients with high-risk stage III or IV
melanoma after surgical removal.
Local principal investigator (PI): Kari Kendra, MD, PhD
- A national phase III trial comparing dabrafenib plus trametinib to
vemurafenib in patients with unresectable or metastatic melanoma that is
BRAF V600E/K mutation-positive.
Local PI: Thomas Olencki, DO
- The High-Dose Aldesleukin (IL-2) “Select” Trial: A multicenter
prospective tissue-collection protocol to investigate predictive models
of response to high-dose interleukin-2 (IL-2) treatment in patients with
Local PI: Thomas Olencki, DO
A multicenter phase III trial of sentinel lymphadenectomy and complete
lymph node dissection vs. sentinel lymphadenectomy alone in patients
with evidence of metastases in the sentinel node.
Local PI: Doreen Agnese, MD
– A national study of minimally invasive inguinal lymph node dissection
for patients with melanoma is determining whether an educational
training program is successful in teaching surgeons a new operative
technique and whether that technique is safe for patients with melanoma
in an inguinal nodal basin.
Local PI: Alicia Terando, MD
refer a patient or check on accrual status, please call The James Line
New-Patient Referral Center toll free: 1-800-293-5066.creasing the
number of National Cancer Institute (NCI)-funded trials and the number
of trials initiated by OSUCCC – James investigators.”
Clinical innovations in melanoma care at the OSUCCC – James are closely tied to the work of translational scientists such as Gregory Lesinski, PhD. Lesinski and his laboratory team are studying interactions between the host immune system and tumor cells in hopes of developing therapeutic or chemopreventive treatments and to improve existing therapies. That work includes collaborating with other OSUCCC – James investigators to develop small-molecule inhibitors that target oncogenic pathways such as STAT3 and XPO1.
“We have discovered that structural derivatives of the natural product curcumin are potent inhibitors of the STAT3 pathway, and we are testing optimized versions of these compounds,” Lesinski says. “We hope to gather data that will allow us to develop drugs with potential for clinical-trials testing.
“Another project focuses on a small molecule that targets a nuclear export protein called XPO1, which has undergone preclinical testing in our lab. We have discovered that it has cytotoxic activity against melanoma cells both in vitro and in animal models, so we are pursuing a clinical trial of this drug in an expanded cohort of melanoma patients.”
Another project involves PRMT5, a protein expressed at higher levels in melanoma than in normal skin. “Knocking down this protein by siRNA (small interfering RNA) in human melanoma cell lines leads to effects on cell growth,” Lesinski says. (siRNA is designed in the lab to interfere with messenger RNA so the cell can’t make the protein.)
Lesinski says an OSUCCC – James research team led by Robert Baiocchi, MD, PhD, is developing small molecule inhibitors against PRMT5, “which we plan to test preclinically as a potential new drug target in a subset of melanomas.”
Constant communication between basic scientists and clinicians allows for sharing data on key oncogenic pathways “that might support acquiring new compounds for the clinic,” Lesinski says. “This interaction enables us to rapidly translate research findings to clinical trials so patients can benefit from cutting-edge science in real time.”
Phuong Hoang, MSN, RN, CNP, and Nancy Stasik, PA-C, help support the medical oncology clinics led by Kendra and Olencki and several other functions. For example, they collaborated with Ohio State’s Pharmacy Department on a retrospective review of supportive-care measures for melanoma patients receiving chemotherapy.
Hoang also leads a monthly melanoma support group through the OSUCCC – James with active patient, physician, psychologist and nutritionist involvement. “We have received very positive feedback and want to make this group known to other patients in central Ohio,” she says.
In conjunction with The Melanoma Research Foundation, Hoang coordinates an annual Melanoma Patient Education Symposium hosted by the OSUCCC – James to present the latest in melanoma prevention, diagnosis and treatment. The second annual symposium was held May 4; the third is set for April 26, 2014.
“We have received much positive feedback from these free symposiums,” Hoang says, adding that feedback drives the agenda. “The first-year attendees wanted more support information, such as symptom management, psychological support and patient testimonies. We provided that this year.”
The OSUCCC – James also hosts a melanoma symposium for referring physicians to increase awareness of the melanoma program. This symposium draws more than 125 attendees from five states. “We anticipate the next one will be in February 2014,” Kendra says.
Kendra and Olencki believe continued educational efforts about the dangers of melanoma and ways to prevent it, along with ongoing development of better therapies—especially for later-stage disease—give patients and referring physicians reason to hope.
“We are able to see new patients quickly, usually within five or six business days of the call,” Olencki says. “We are very attentive to getting patients in for comprehensive care as soon as possible.”
“We are making progress against melanoma,” Kendra adds. “We’ve gone from therapies that help a small number of people for a short time to therapies that help a larger number of people for a short time. With additional research, we will develop more therapies that will help larger numbers of people for longer periods of time and bring about better outcomes.”