Melanoma International Foundation Blog

William Conway, MD
Donald L. Morton, MD, FACS; MIF Scientific Advisory Board
John Wayne Cancer Institute at Saint John’s Health Center, Santa Monica, CA

Although new drugs and drug combinations have produced dramatic results in many advanced malignancies, they have been disappointing in metastatic melanoma. Patients with disseminated (stage IV) disease have a median survival of only about 6 months. In these patients, surgery often offers the best chance for symptom relief and possibly cure. However, its success depends on careful patient selection, which is why clinical investigators in the melanoma program at the John Wayne Cancer Institute (JWCI) have conducted extensive studies to define the indications and prognostic factors for surgical resection of melanoma to distant sites.

Stage IV metastatic melanoma is divided into three groups by the American Joint Committee on Cancer (AJCC) staging system. M1a disease comprises metastases of the skin, soft tissues, and distant lymph node basins. This is the most common form of stage IV melanoma and carries the best prognosis: median survival is 10-18 months, increasing up to 24 months with complete surgical resection. Surgical therapy is also appropriate for palliation of symptoms; resection can relieve the pain caused by large soft-tissue masses, and it can eliminate impaired extremity motion due to bulky nodal disease in the axilla or groin.

When melanoma has metastasized to the lungs, it is referred to as M1b disease. Patients with lung metastases generally have an overall median survival of 10 months or less. However, surgery can significantly improve prognosis: median survival of 20-25 months has been reported with complete metastasectomy; 5-year survival rates are 25% or more. Factors predicting prolonged survival after resection include a prolonged tumor doubling time and only 1 or 2 metastatic nodules. Tumor doubling time (TDT), defined as the time required for a mass to double in size, is an important selection criterion for surgery because it is directly related to outcome: the longer the TDT, the less aggressive the tumor and therefore the better the survival.

M1c disease refers to melanoma metastatic to other visceral sites. This includes bowel, liver, adrenal glands, other intra-abdominal organs, and the brain. Median survival in this group is generally less than 8 months, but again an aggressive approach to surgical therapy can significantly improve the prognosis of selected patients. Several series report median survivals of 24-35 months, with 5-year survival rates of 25-35% after complete metastatic resection. Even when not all tumor can be removed, palliative surgery can relieve crippling symptoms caused by bowel obstruction, bleeding, and abdominal pain. For example, resection of small bowel metastases can end the chronic blood loss from these lesions, alleviating the symptoms of fatigue and light-headedness associated with anemia.

The success of aggressive surgery for stage IV melanoma not only reflects the efficacy of surgical techniques, anesthesia, and postoperative care, but also the sensitivity and accuracy of preoperative/intraoperative imaging studies used to stage and assess disease. Computed tomography (CT) can clearly delineate metastatic lesions amenable to resection; positron emission tomography (PET) allows detection of diffuse disease that may be suitable for palliative resection to control symptoms.

Surgery is not for all cases of stage IV melanoma, but it can be extremely successful in a carefully selected subgroup. In particular, patients with a prolonged TDT, few and/or isolated metastatic deposits, and no comorbidities may be excellent candidates. It is important to remember that incomplete resection does not confer a survival advantage and should be planned only in an effort to relieve symptoms due to mass effect. The success of complete metastasectomy was confirmed in a recently completed phase III randomized multicenter trial. In this study, patients with stage IV melanoma underwent complete surgical resection and then were randomized to one of two immune-based adjuvant therapies. When data from both treatment arms were combined, median survival reached an impressive 34.9 months and 5-year survival rate was 40%. These statistics are unmatched by any randomized trial of medical therapy for stage IV melanoma, and they support our firm belief at JWCI that early surgical evaluation is mandatory to offer the best possible chance for long-term survival after a diagnosis of stage IV melanoma.

by Keith Flaherty, M.D. Co-chair MIF Scientific Advisory Board

Deciding whether or not to pursue medical therapy following the surgical removal of melanoma (“adjuvant therapy”) is a complex and individual choice. There are three important factors that strongly influence this issue: the thickness of the primary melanoma, the presence or absence of microscopic ulceration, and the involvement of lymph nodes. Generally, surgery to assess the potential involvement of lymph nodes is only recommended if the primary melanoma is at least 1 mm in thickness or there is evidence of microscopic ulceration.

Adjuvant therapy is considered potentially appropriate only if the primary melanoma is at least 2 mm in thickness (thinner in the presence of microscopic ulceration) or there is evidence of melanoma in the lymph nodes. Even the presence of melanoma in lymph nodes is not an entirely straightforward issue, as the presence of a few melanoma cells in a single sentinel lymph node may be no more worrisome than no evidence of melanoma cells at all. In the end, discussion of the features described above and the potential need for adjuvant therapy should be discussed with a medical oncologist to determine the most appropriate course.

The only FDA approved therapy to prevent recurrence of melanoma following surgical removal is one year of “high-dose” interferon alpha. This therapy can possibly delay a potential recurrence of melanoma. However, it is less clear that people who take interferon live longer than those who do not. While there is no doubt that interferon impacts the risk of melanoma recurrence, to some degree, the treatment is associated with severe side effects in most who take it. Therefore, the decision to take interferon or not requires careful consideration of the potential benefits and risks.

A major focus of melanoma research is to develop more effective and tolerable adjuvant therapies. While several types of therapies are being investigated, the largest number of clinical trials in this area are evaluating melanoma vaccines. In general, vaccines have been associated with very infrequent and mild side effects. However, no vaccine has demonstrated an ability to either delay the recurrence of melanoma or contribute to longer survival. Therefore, trials with vaccines or other novel therapies must be considered experimental. The availability of clinical trials with novel adjuvant melanoma therapies varies over time and may require travel to a cancer center that is participating in these trials. A medical oncologist will be able to determine if a trial is available.

by Dr. Keith Flaherty, M.D.

A study by the American Academy of Dermatology(AAD) showed that a patient needing a cosmetic appointment with a dermatologist could get into the office in just eight days. However, when they requested a mole check, a typical wait of 26 days was in order. The study by Dr. Jack Resnick, assistant professor of dermatology at the medical school of University of California at San Francisco, was enlightening and disheartening.

A researcher posing as a patient called every board certified dermatologist in the 12 cities. Seattle had a median Botox wait of almost eight days to get an appointment, whereas there was a 35 day wait for a changing mole.

Patients often call MIF with this complaint that they can't get a timely appointment with a dermatologist. We urge them in our education programs to get to a dermatologist promptly if they find a changing mole, and then they hurry up to wait! The president elect of the AAD said it seemed obvious that cosmetic patients had faster access to dermatologists than did medical patients. One explanation was that the demand for medical dermatology outstrips the supply. Others, however, tend to agree that it is the financial incentive driving the market. The charges for a Botox anti-wrinkle treatment is $400 to $600. And of course, health insurance doesn’t cover a penny of it, so patients pay up-front. Doctors don’t have to deal with insurance companies to reimburse them for the Botox as they do with suspicious mole exams.

We at MIF urge dermatologists to please consider the personal anguish patients face when they think they may have melanoma. The waiting for a skin exam can be very stressful. No one knows how fast melanoma grows as well, so waiting can be risky. To put profit before patient is certainly against any Hippocratic Oath taken when you become a doctor.

Dr. Keith Flaherty, M.D.

For melanoma that is limited to the skin, surgery alone is capable of curing melanoma in the vast majority of individuals. When melanoma has spread to lymph nodes, surgery alone is helpful. However, there is a substantial risk that melanoma could resurface. For that reason medical therapy following surgery (“adjuvant therapy”) is considered. Interferon remains the only FDA approved adjuvant therapy for melanoma that involves lymph nodes or is very advanced in the skin alone. However, based on numerous clinical trials, only one in ten people who take interferon have the recurrence of melanoma prevented.

For melanoma that has spread to lymph nodes or internal organs there is a profound need for better therapies. Many clinical trials are currently being performed for the treatment of melanoma. It is in the context of these trials that individuals can gain access to experimental treatments that are not yet FDA approved.

Clinical trials differ greatly in their design and the considerations regarding participating in a clinical trial vary from trial to trial. As a general statement, clinical trials are evaluating a new therapy that is not yet proven to be effective. In this case, proof is the level of evidence required by the Food and Drug Administration to support the claim that a therapy is both safe and effective. For cancers therapies, new therapies usually have to show that they are superior to previously available therapy.

Most therapies that eventually gain FDA approval spend an average of 7-8 years in clinical trials. During that time the number of patients treated and the knowledge gained about a therapy increases greatly. Therapies that being tested in phase III trials, the last step prior to FDA approval, have already shown some sign of promise in earlier trials.

Phase III trials are generally comparing a new therapy to an established therapy. In order to determine if this is the case, therapies are directly compared among people with the same stage of melanoma, at the same time. In order to have confidence that new therapies do not appear better due to physicians assigning patients with a better prognosis to one therapy over another, patients are randomly assigned to receive one therapy or another. If at any time during the trials, results are obtained that established one therapy to be better than the other, the trials is stopped and all patients are offered the superior therapy. In many cases, trials only prove a difference well after all patients have received their entire course of treatment and additional time has passed.

Phase II trials are typically the first evaluation of a new therapy in a certain type of cancer. Of note, many new melanoma therapies are evaluated only in melanoma patients even in phase I testing because they are thought to only be potentially effective for melanoma. Phase II trials can be designed so that everyone received the same therapy, or can randomly assign patients to receive the new therapy in one of several different ways, or to a standard therapy. In that sense, phase II trials can occasionally be designed in a way that seems like a phase III trial. The difference is that phase II trials are generally not designed to provide definitive evidence to support FDA approval.

Phase I trials can involve a new therapy that is being evaluated in humans for the first time or can the be first time that two or more previously tested or proven therapies are being evaluated together. So, phase I trials do not always contain entirely new therapies. Therapies that are being evaluated for the first time in humans usually have to be tested at different doses to determine what dose is safe and potentially effective. Typically near the end of phase I trials, the safe dose has been determined, but additional patients are treated to gain more confidence that this is the case.

The most important thing to note is that the “best” or most promising therapies are not necessarily those in phase III trials compared to phase II or phase I trials. The phases usually only indicate how long a therapy has been in trials. For some revolutionary new therapies for other cancer, drugs in phase I trials were showing better results than any other therapy in phase II or phase III trials. The key point is that clinical trials offer access to therapies that are not yet generally available. How attractive one trial will be over another depends a lot of the nature of the therapy in the trial and the experience with that therapy to date. A medical oncologist should be able to guide this discussion to help sort some of the complexities of sorting out which trials might be worth pursuing.

Another key element to consider regarding clinical trials is geographic. Most phase III trials are being conducted and hundreds of cancer centers, which means that the distance that any one person would have to travel in order to participate is minimized. Phase II trials are typically conducted in as few as one center or as many as twenty to thirty. Phase I trials are generally conducted at one to three cancer centers at a time. For this reason alone, the availability of certain phase II and phase I trials is going to depend alt on the ability to travel to a center that is conducting those trials. There are cancer centers that conduct melanoma trials throughout the country, but the distribution of cancer centers closely parallels population density. Therefore, patients on the East Coast, California and Texas tend to have the greatest number of centers in their area that conduct melanoma trials.

The only resource that is readily available and frequently updated with basic information about melanoma trials is the National Cancer Institute’s web site, www.clinicaltrials.gov. This site includes all trials that are being financially supported by the National Cancer Institute, but also lists most trials that are being supported by pharmaceutical companies. Trials that are most likely to be missing from this listing are those trials occurring at just a few cancer centers (phase II or phase I).

By Bruce Brod, MD
Co-chair MIF Scientific Advisory Board,
Professor of Dermatology UPenn

Fifteen minutes at a tanning salon equals a full day at the beach. Exposure to ultraviolet light (UV) is one of the most preventable risk factors for the development of melanoma. In the past most people received most of their exposure to UV light from the sun. Currently much of this exposure stems from the use of indoor tanning salons. The ultraviolet light from indoor tanning salons is similar to that from the sun. The difference is that 15 minutes of UV light in a tanning salon creates as much damage to the skin as a full day at the beach.Tanning salons have targeted our teenagers and young adults in their marketing strategies. On an average day in the United States, more than 1 million people enter a tanning salon. Of those customers, 70 percent are Caucasian girls and women, aged 16 to 49 years. In a 2002 study published in the Journal of the American Academy of Pediatrics, approximately seven percent of girls aged 14 reported they had used tanning beds in 2001, while 16 percent of girls age 15 had reported doing so. By age 17, the statistic increased to 35 percent of girls who had used tanning beds. According to a 2002 study published in the Archives of Dermatology, 47 percent of students at a Midwestern university had used tanning beds in 2001. Of those surveyed, 90 per cent also admitted to knowing that tanning is a health risk, yet they continued to use tanning beds frequently. There are a number of studies including a Swedish study that present strong evidence that indoor tanning increases the risk of melanoma, especially when indoor tanning begins at an early age.

In Pennsylvania, we have been working with legislators for years in an effort to enact legislation to regulate and restrict access to indoor tanning salons. There are currently only 25 states that regulate youth access to indoor tanning despite support from the World Health Organization, the American Academy of Dermatology Association, the American Medical Association, the American Academy of Pediatrics, and Melanoma International Foundation to ban the use of indoor tanning equipment by anyone under the age of 18. A goal should be for no minor to use a tanning device. There should be a Surgeon General’s warning on all tanning devices. Tanning salons should not be allowed to advertise indoor tanning as “safe”, using words that include “no harmful rays”, “no adverse effect”, or similar wording concepts.