Advances in treatment for the deadliest form of skin cancer are aligning, bringing patients new hope

By Michele Conklin

Shannon Clark is a melanoma patient at the University of Colorado Cancer Center

Shannon, with her children

Sitting around the dinner table each night, Shannon Clark and her three children play a game they call “High-Low” when each person shares the high point and the low point of their day.

On Jan. 26, Clark’s high and low points came in one phone call. Her oncologist, Karl Lewis, MD, at the University of Colorado Cancer Center in Aurora, had phoned her with bad news. Her stage IV melanoma had progressed and she had a large stomach tumor that was blocking one kidney from functioning.

The news came 17 months after she was diagnosed–a miracle amount of time in the world of advanced melanoma where there is no cure and patients live only nine months on average. Still, a blink of time when you’re a single mother raising three children. It was definitely a low moment. But it was what Lewis said next that Clark clung to.

“I have something for you,” he told Shannon. “We’re opening a trial that has shown some good results and there’s a spot for you.” “It wasn’t just his words, it was the tone of his voice, the excitement in his voice, that gave me hope,” Clark, 34, of Fort Collins, says.

Delicate decisions

Nearly 70,000 people in the United States will be diagnosed with melanoma this year, according to the American Cancer Society. The vast majority will have early stage melanoma that is cured by removing it from the skin.

But when melanoma spreads into the lymph nodes or organs, there is no cure. Only two drugs have ever been approved to treat melanoma: dacarbazine and Interleukin 2. But these drugs have never actually been shown to improve overall survival in randomized clinical trials. Fifty percent of patients treated with these drugs survive past one year–the same percentage of people who receive no treatment at all.

Hope for these patients lies in clinical trials of new drugs. Determining which drug to use, however, becomes a bit like solving a Rubik’s cube where each twist counters another. Physicians have to understand all the trials currently available, as well as those that are soon to open and the requirements for each, so that they can organize treatments in a sequence that will not preclude the patient from being eligible for a different treatment down the road. The goal is to eke out weeks and months of quality life before the cancer recurs, while always leaving another option in reserve.

“The question always is: What do we do next?” says Lewis, an assistant professor of medical oncology at the University of Colorado School of Medicine (SOM) who specializes in melanoma. “It’s never easy. We try to leave as many doors open as possible. Unfortunately, some patients come to us after they’ve been treated with something we know to be ineffective that then excludes them from a trial.”

Last year, CU Cancer Center’s melanoma program treated more than 450 new patients, ranking it as one of the top centers in the country with M.D. Anderson and Memorial-Sloan Kettering. These centers not only treat patients, but they are also the leading research institutes conducting clinical trials at every level into new treatments for melanoma. CU Cancer Center members also conduct laboratory research in areas such as identifying strategies to overcome melanoma resistance to treatment, and can quickly adapt research back and forth from lab to patients.

First real breakthroughs

Clark was first diagnosed with melanoma in 2003 when a cancerous spot was removed from her shoulder. Like 98 percent of people diagnosed with melanoma that has not spread, Clark was considered cured.

Five years later–almost to the day–Clark felt a bump on her head. She wasn’t worried about cancer because her latest x-rays and blood tests at the oncologist were clear. Because she worked at a radiology facility, she decided to have the bump scanned just in case.

“That was the day my life as I knew it changed forever,” says Clark, a petite woman with blonde hair and fair skin who remembers getting badly burned while growing up in Estes Park. Sunburns are one of the known risk factors of skin cancer. Clark decided to first try a holistic approach. She eliminated meats, processed foods and sugars from her diet, and added large doses of vitamins. Within two months, however, with her cancer continuing to grow, she decided to try biochemotherapy–a vicious regimen of five chemotherapy drugs that requires hospitalization for five days every three weeks.

“If you weren’t scared when you were told you had melanoma, you were when they told you about this,” Clark says. “But I was ready to beat this monster for my kids. I came with my fighting gloves on.”

Although controversial due to unreliable outcomes and severe toxicity, biochemotherapy may result in a response in some patients. Clark was one of those few–her tumors stopped growing after the second round.

She received seven rounds of biochemotherapy at University of Colorado Hospital–CU Cancer Center’s adult clinical partner–followed by eight months of reduced biochemotherapy maintenance before her cancer started growing again. By January, she had lived twice as long as the statistics predicted.

“No one can tell me how long I have to live,” says Clark, sitting in a conference room at the Cancer Center with her children–15-year-old Shane, 10-year-old Blake and 8-year-old MacKenzie. “You don’t know; I don’t know. All we know is what we have today.”

And what Clark was offered that day in January when her cancer returned was a new drug that was showing promise in other melanoma patients. “At that time, physicians were talking about seeing results in days,” Clark says. “From day one (on the trial drug), my stomach (tumor) started melting away.”

The drug Clark was put on, still in clinical trials, is known as PLX4032. The drug blocks the action of a gene known as BRAF that is mutated in about half of melanoma patients. Now entering the last phase of clinical trials, the drug appears to stop the disease from progressing for about six to nine months, Lewis says.

“The reality is that this cancer will probably find a way around most drugs,” he says. “Although we are always searching for a cure, it may be more realistic to turn cancer into a chronic disease, like diabetes, that you don’t cure but rather you manage.”

Attacking two fronts

CU Cancer Center is one of just 14 centers in the world–and the third largest test site–with access to PLX4032. That trial is one of about a dozen melanoma clinical trials that the center is currently conducting.

“It’s an exciting time in melanoma research,” says Rene Gonzalez, MD, director of the melanoma program and professor of medical oncology at the SOM. Gonzalez doesn’t make that claim lightly. This is the first time in his 25 years of specializing in melanoma that he’s seeing treatments make a difference.  Interleukin 2 was the last drug to be approved for treatment–in the mid-1990s. Even then the drug showed no improvement in survivability over doing nothing.

Researchers are making advances on two fronts–molecular biology and immunology. The molecular biology drugs attempt to identify and  block genetic mutations that cause cancer. Immunology treatments seek to use the body’s natural defenses to fight the cancer. CU Cancer Center recently participated in the Phase III trial–the final test before a drug is considered for widespread use–of an immunologic drug that shows the first-ever survival benefit in melanoma patients. The drug, called ipilimumab, allows the body’s immune system to continue to fight the cancer cells.

“This is the only drug that has ever shown improved survival results in melanoma,” Gonzalez says. “And we have it right now (at CU Cancer Center), even before it’s been approved by the FDA.”

Expanding trials to more patients

Currently, CU Cancer Center is collecting data for approximately 500 clinical trials in 10 cancer areas, including melanoma, with between 150 and 200 of those open to enrollment of new patients, says Andrea Buchmeier, director of clinical research. The clinical research program has doubled in number of trials, number of enrolled patients and number of staff in the past six years, she says.

And still that’s not enough.

“It’s difficult to tell a patient that they can’t get into a trial or that a trial is not open yet,” says Mary Cook, BSN, the clinical research coordinator for melanoma trials. “It’s heart-breaking when you know that this person may die before you can get the trial open.”

Cook and her staff work side-by-side with the medical team and patients, ensuring that every appointment is scheduled, lab test conducted and reaction recorded. Inevitably, that means becoming close to patients–in bad times and in good.

“We’re treating a woman who went from lying in bed in a fetal position to being up and about for the past seven months,” Cook says. “Seeing that kind of improvement in quality of life keeps you going.”

As is so often the case in health care, funding is always an issue. The cancer clinical research program has an annual budget of $5 million and runs in the red every year. About 40 percent of the clinical trials are paid for by pharmaceutical companies. The remaining 60 percent are unfunded or underfunded trials initiated by CU physicians, by other cancer cooperative research groups or by the NCI.

“There’s this misconception that drug companies pay for all our research,” Buchmeier says. “But the majority of our work is trials that our physicians or physicians from other cancer centers have written that could fundamentally change how we treat cancer. It’s what makes us a comprehensive cancer center.”

In the past 15 years, the melanoma program has enrolled more than 1,200 patients on clinical trials, including patients from as far away as London and Amsterdam. The melanoma clinic will log more than 4,500 patient visits this year.

Mary Cook and Andrea Buchmeier make sure cancer clinical trials go smoothly on all fronts. Trials of new drugs are the bedrock of modern cancer care.

“When you see that many patients and you participate in that many trials, you offer patients the greatest chance of finding something that works,” Gonzalez says. “We’re in line to get drugs that are not even in clinical trials yet.”

Gonzalez doesn’t take sides in whether he thinks the biggest breakthrough will come from the genetic therapies or the immunologic therapies. “I’ll use whatever drug works,” he says.

For Clark, the drug that is working for now is PLX4032. And if that stops working? She’ll think about that when the time comes.

“I embrace what I have right now,” she says as she smiles across the table at her children.