Melanoma International Foundation Blog

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).