New Approaches for Advanced Melanoma

iFrom OncoLog, March 2007, Vol. 52, No. 3
New Approaches for Advanced Melanoma
by Sunni Hosemann

Dr. Elizabeth Grimm (l) and Dr. Patrick Hwu discuss new avenues in melanoma research. When a melanoma is found early and properly removed, the outlook is excellent. In fact, patients with early-stage melanoma can have survival rates as high as 95%. But for patients with melanoma that has metastasized, the disease is more deadly: the survival rate for patients with metastatic melanomas involving a major organ is no more than 6%—evidence that today’s clinicians have a challenge in finding ways to better manage advanced forms of the disease.

Currently, only two FDA-approved drugs exist for the treatment of metastatic melanoma: dacarbazine and interleukin (IL)-2. Dacarbazine is a conventional cytotoxic chemotherapy agent. According to Kevin Kim, M.D., an assistant professor in the Department of Melanoma Medical Oncology at The University of Texas M. D. Anderson Cancer Center, the rate of response to dacarbazine in metastatic melanoma is only about 10%, and it rarely produces a durable response. And although combination regimens that include dacarbazine have been investigated, none have improved survival more than dacarbazine alone.
On the other hand, IL-2, which works by stimulating killer T-cells to attack melanoma, produces a response in 15% to 20% of patients; in 7% to 8% of patients, the response is durable.

“We can essentially cure some patients with advanced disease using IL-2, but only a small minority of patients have this remarkable response. We want to know why,” said Patrick Hwu, M.D., professor and chair of the Department of Melanoma Medical Oncology. Knowing ahead of treatment who is likely to respond to IL-2 would spare the majority of patients with advanced melanoma from undergoing a treatment that can be toxic and must be delivered in the ICU. “Beyond that,” said Dr. Hwu, “if we can understand how it’s working, perhaps we can convert non-responders into responders.”
Clearly, other treatments are also needed for those who are unlikely to respond to either of these two agents, both of which are toxic and costly. To that end, investigators are pursuing several promising avenues.
Ideal candidate for immunotherapy

Dr. Hwu believes that certain factors make melanoma an ideal candidate for therapies based on the immune system. “When you remove a melanoma,” he said, “you find immune cells there already trying to attack it.” On that basis, Dr. Hwu and colleagues at the National Cancer Institute pioneered a treatment approach currently in use, in which adoptive T-cells are harvested from the patient’s tumor, grown in the lab, and reintroduced to attack the tumor in greater numbers. In a current study of this method in patients with advanced or recurrent melanoma, half of the tumors responded.

Vaccine therapy is a second immune-based approach, one that Dr. Hwu expects may be of greatest benefit in preventing recurrence, perhaps in combination with other therapies that attack active disease. “With initial therapy, patients may reach a point where they have no identifiable disease, but we know the cancer might come back, and this is where a vaccine might help keep the disease at bay,” he said. In current trials, vaccine therapy is being used in combination with other kinds of agents to see if this dual approach is helpful.
Accurate staging is key, says Dr. Jeffrey E. Gershenwald (r), discussing a case with Mary Salazar, a nurse. Another avenue of research focuses on combining targeted therapies to achieve a synergistic response. Although individual targeted agents have failed to improve response rates in melanoma, preclinical data have recently shown that combinations of targeted agents have promise. “One of our focuses is looking at combination strategies that use targeted agents to block receptor proteins in melanoma cells,” Dr. Kim said. Such combinations might include more than one targeted agent or a targeted agent plus a chemotherapy agent.


According to Dr. Kim, gene transfer is yet another promising line of inquiry. As a result of the work of Elizabeth Grimm, Ph.D., a professor in the Department of Experimental Therapeutics and leader of the Melanoma SPORE grant at M. D. Anderson, Dr. Kim is leading a trial using a virus expressing IL-24, a member of the IL-10 family with both tumor suppressor and proinflammatory properties. “Dr. Grimm and her colleagues have observed that as melanoma progresses, the cells lose their expression of the IL-24 gene. Further, they have observed that when the IL-24 gene is reintroduced, the melanoma cells undergo apoptosis,” said Dr. Kim. In a current phase II clinical trial, intratumoral injections of a virus expressing IL-24 are being evaluated in patients with metastatic melanoma who have cutaneous lesions.

Treating “in-transit” disease

A difficulty associated with melanoma is the treatment of “satellite” or “in-transit” disease, which appears as cutaneous or subcutaneous deposits of tumor cells between the primary tumor and the regional lymph node basin. For example, when a primary tumor is on the foot, metastatic lesions between the foot and groin would likely be considered “in-transit.” Some patients, whose satellite lesions become too numerous or bulky to excise, can undergo perfusion, the regional delivery of chemotherapy after the vasculature of the targeted area, usually a lower limb, has been cannulated and isolated.

In a newer version of this approach, known as “minimally invasive isolated limb perfusion” or “isolated limb infusion,” the chemotherapeutic agents are circulated via catheters placed into the affected arm or leg while a pressure cuff device or tourniquet temporarily stops circulation, effectively isolating that area. “Compared to conventional limb perfusion, this evolving approach involves a lower flow rate and an overall shorter duration of circulation, but it can also have significant toxicity,” said Jeffrey E. Gershenwald, M.D., an associate professor in the Department of Surgical Oncology at M. D. Anderson.

Advances in staging: sentinel lymph node biopsy

Accurate staging is critical to the management of melanoma. “One of the recent success stories in this disease is our ability to identify patients with newly diagnosed intermediate- and high-risk melanoma who have no clinical evidence of lymph node involvement but in fact harbor microscopic metastases in their regional lymph nodes,” said Dr. Gershenwald. Combining diagnostic modalities, such as lymphatic mapping and sentinel lymph node biopsy, allows more information to be gathered about the existence and extent of metastases. One such combined approach uses a radioactive tracer injected around the primary tumor site and a blue dye to identify sentinel lymph nodes, the regional nodes most likely to contain evidence of microscopic metastases, which are then removed for pathologic analysis.

According to Dr. Gershenwald, sentinel lymph node biopsy accurately determines the involvement in regional nodal basins, improves regional nodal control, may offer a survival benefit, and has enabled the selection of more stageappropriate treatments. Specifically, the procedure can identify the 15% to 20% of patients with microscopic stage III disease who need additional or more aggressive treatment, such as a complete lymphadenectomy. These patients are also offered adjuvant therapy or the opportunity to participate in adjuvant therapy trials. Even more, if a biopsied node is negative, the patient is spared a complete lymph node dissection.

A key to further progress against melanoma may lie in the increasingly sophisticated study of tumor biology and pathology. In most current trials, any tissue removed is subjected to intense pathologic scrutiny.

With more sophisticated tumor analysis will come more precisely targeted therapies, says Dr. Victor Prieto. “A unique aspect of the sentinel lymph node biopsy approach is that the surgery is based on the biology of the patient’s own tumor environment. It allows us to identify regional lymph node disease that we might not see even with complete lymph node dissection,” said Dr. Gershenwald. He stresses that the success of a sentinel lymph node biopsy includes the identification and removal of the sentinel lymph nodes from all regional basins at risk and the intense histologic analysis of removed tissues.
Traditionally, pathologists have used similar methods to study the stained slices of lymph nodes removed during either complete or sentinel lymph node dissections. However, newer evidence has led pathologists to examine multiple slices from different “levels” of sentinel nodes and use immunohistochemical analyses. According to Dr. Gershenwald, M. D. Anderson investigators are also looking into the potential prognostic significance of microscopic regional lymph node disease.

Insights from molecular pathology

Another key to progress may come from the field of molecular pathology. “We used to think that melanoma was a single entity,” said Victor Prieto, M.D., Ph.D., a professor in the Department of Pathology. “But in the last five years, we have come to realize that isn’t the case at all.”

What investigators have recently realized is that the four major subtypes of melanoma, long-recognized as superficial spreading, nodular, lentigo maligna, and acral lentiginous melanoma, each have a different genetic profile and further, that this genetic profile can be linked to a phenotype. According to Dr. Prieto, this is an important insight because targeted therapies are specific to particular proteins.

For example, imatinib (Gleevec)—the agent used so successfully in chronic myelogenous leukemia—met with limited success in melanoma. But after one patient, whose acral lentiginous melanoma had an alteration in an imatinib-targeted tyrosine kinase pathway and showed a response to imatinib, researchers began examining acral lentiginous and mucosal melanomas for alterations in the same pathway to determine whether patients with these specific phenotypes might also respond to therapy with imatinib.

“This is similar to the Herceptin story for breast cancer, where only 25% of patients have HER2/neu receptors, and only those tumors are expected to respond to that specific therapy,” said Dr. Prieto. “It seems clear that as the biological and pathologic analysis of tumors grows more sophisticated, the targets for targeted therapies will also become more precise.”

In addition to leading to more targeted therapies, analyses using molecular pathology can yield more precise prognostic information, an important guide in making treatment decisions. According to Dr. Prieto, “The information allows us to better determine who should receive additional therapy—patients who have a higher risk of recurrence or metastasis, for example—and whether additional therapy will confer a survival benefit.”

Broader implications

Dr. Hwu and his colleagues at M. D. Anderson believe that melanoma research will have broad implications for other cancers, especially because cutaneous melanoma metastases are readily accessible for biopsy and study. This makes it easier for researchers to study key disease characteristics, such as whether a certain kind of tumor responds to certain drugs, whether a therapeutic target was hit, whether a signal pathway was effectively blocked, and whether a particular switch was successfully turned on or off.

By seeking answers to these questions and more, melanoma researchers are going beyond “skin deep,” gaining knowledge that may advance treatment not only in the field of melanoma but in other diseases across the spectrum of cancer.

Jimmy B.