Becoming more and more common‚ melanoma is challenging cancer if not caught early

By Lynn Gentry

According to the National Cancer Institute (NCI)‚ Bethesda‚ Maryland‚ melanoma accounts for about 4% of skin cancers diagnosed annually‚ but the number of people developing melanoma is increasing faster than any other form of cancer. Since 1973‚ the incidence rate for melanoma (the number of new melanomas diagnosed per 100‚000 people each year) has more than doubled from 5.7 to 14.3. This means 53‚600 new melanomas were diagnosed in the United States during 2002 and around 7‚400 people died.

Surgical excision often cures melanoma caught in its earliest stages.Indeed‚ the five-year survival rate for early-stage melanoma is better than 90%.

However‚ if melanoma is diagnosed when it has penetrated the deeper levels of the skin or spread to other parts of the body‚ the prognosis is significantly impacted. Once in the lymphatic system‚ melanoma can travel via the bloodstream to the bones‚ lungs‚ liver‚ brain‚ or other areas. The five-year survival rate for stage IV melanoma‚ meaning the tumor has spread to other organs or to lymph nodes far away‚ is only about 5-6%.

“Melanoma gives cancer a bad name‚ but we have to be more positive about the many treatment options available to patients today‚” says John Kirkwood‚ MD‚ director of the Melanoma Program‚ University of Pittsburgh Cancer Institute (UPCI)‚ Pittsburgh. “Otherwise‚ some people won’t pursue the help that’s available‚ and we won’t learn what we need to win the battle.”

When melanoma starts in the skin‚ it is called cutaneous melanoma. Melanoma may also occur in the eye (ocular melanoma or intraocular melanoma) and‚ rarely‚ in other areas where melanocytes‚ the pigment-producing part of the skin‚ are found‚ such as the digestive tract. When melanoma spreads (metastasizes)‚ cancer cells are also found in the lymph nodes and possibly also other parts of the body‚ such as the liver‚ lungs‚ or brain. In these cases‚ the cancer cells are still melanoma cells‚ and the disease is called metastatic melanoma.

Has It Spread?
If a physician suspects melanoma‚ he or she will remove a sample for examination. If the growth is cancerous‚ a second surgery removes the remainder of the area and additional tissue‚ or margins‚ around the original cancer site for further examination. Doctors evaluate the thickness of the melanoma—thick lesions signal a risk for metastasis—and the presence of ulceration‚ another sign of increased risk of relapse and mortality.

Next‚ the patient’s lymph nodes will be examined. Historically‚ this required removal of all the lymph nodes near the primary cancer site. However‚ Donald L. Morton‚ MD‚ medical director and surgeon-in-chief at John Wayne Cancer Institute‚ Santa Monica‚ California‚ developed a procedure called sentinel lymphatic mapping that uses a special dye and/or radioactive agent to track the flow of lymphatic fluid to ascertain which lymph node(s) might be the first to receive cancer cells from the primary tumor. Once the so-called “sentinel nodes” are identified‚ surgeons can remove only these few nodes. If the sentinel nodes are clear of cancer cells‚ doctors have greater confidence the cancer has not spread.

“Sentinel node dissection is not completely reliable‚ so doctors in Europe and the United States have worked for years to develop blood tests to detect selected proteins and molecular markers that can indicate subclinical metastasis‚” says Dr. Kirkwood.

Standard Treatment for Malignant Melanoma
For patients whose melanoma is diagnosed in stage 0 or I‚ surgical excision usually solves the problem.

For patients with stage II (broken down into A‚ B‚ and C)‚ the options become more complex. Following surgery‚ some doctors advise waiting and watching for patients with stage IIA melanoma‚ hoping that any stray cancer cells might be handled by the body’s immune system.

Doctors have long recognized that cancer weakens the immune system‚ so within the last decade‚ doctors have concentrated on increasing the immune response to cancer. Cancer researchers are primarily interested in stimulating production of T-cells‚ the lymphocytes in the blood system that regulate and activate the body’s response against foreign agents and diseases. Scientists have found that several naturally occurring substances in the body called cytokines‚ which include Intron® A (interferon) and Proleukin® (interleukin-2 or IL-2)‚ can increase T-cell activity and signal the body to produce more T cells.

“After 20 years of research‚ the only drug we’ve found that’s significantly effective against melanoma in the adjuvant setting is interferon‚” says Dr. Kirkwood. “Interferon can work directly on cancer cells by interfering with how the cells grow and multiply‚ and it encourages killer T cells and other white blood cells to attack cancer cells. It also encourages the cancer cells to release chemicals that attract the immune system cells to them.”

Doctors frequently recommend high doses of interferon for one year for patients with stage IIB or stage III melanoma—possibly mixed with some investigational vaccine therapies—to coax the body into wiping out the cancer before it spreads any further. Doctors at UPCI have recently launched a phase III international trial in patients with stage IIA melanoma with a four-week course of intravenous interferon.

“We’re trying to address the problem earlier‚” says Sanjiv S. Agarwala‚ MD‚ associate medical director. “We’re comparing the outcomes of patients receiving the short course of interferon with those who simply watch and wait following surgery to see if we can actually reduce recurrence. The patients in this trial are courageous‚ since they normally wouldn’t be taking interferon at this stage. Some are receiving placebos‚ and some are putting up with the side effects for the sake of others.”

Frank Lovrich‚ 75‚ of Jeanette‚ Pennsylvania‚ is one of those patients. He was diagnosed with melanoma in 2001 after a dermatologist removed a dark spot on his ear lobe that caught the attention of both his doctor and dentist.

“I was glad to take part in the study‚” he says. “Anyone in my situation would be foolish not to take the opportunity. It gives you a greater sense of control over a disease that can get out of control quickly if it comes back.”

For patients with advanced stage IV melanoma‚ doctors use all the options at their disposal. A common treatment is chemotherapy‚ typically a regimen of DTIC® (dacarbazine) or a combination of DTIC and other chemotherapy drugs such as Platinol® (cisplatin)‚ Oncovin® (vincristine)‚ Velban® (vinblastine)‚ and others that form a multi-pronged approach. These drugs kill cancer cells by interfering with the synthesis of their genetic material‚ which prevents the cells from reproducing. However‚ none of these drugs alone or combined achieve more than a 25% response rate‚ and the long-term survival rate is not impacted.
Radiation therapy is used for bone or brain metastases. Doctors can surgically remove metastases in the lungs‚ central nervous system‚ and soft tissues. However‚ patients frequently develop other metastases.

“We certainly have more options today for melanoma patients than we did 10 years ago‚ but as the cancer spreads‚ it presents greater challenges‚ since the standard chemotherapy drugs and therapy protocols don’t work as well in all cases‚” says Dr. Kirkwood.

For patients with melanoma metastases in the brain‚ Dr. Kirkwood’s team has developed a new therapy using the oral chemotherapy drug Temodar® (temozolomide). Temodar is similar to DTIC‚ which cannot be used against brain tumors because it does not enter the brain in high concentrations. Temodar‚ on the other hand‚ easily diffuses into the fluid spaces of the brain and has shown some success in shrinking brain tumors.

“We haven’t been able to shrink brain tumors with other chemotherapeutic agents‚ so this is progress‚” says Dr. Kirkwood. “Because temozolomide is an oral drug‚ administration is also easier on patients.”

Doctors at the NCI are taking another approach to stage IV melanoma‚ administering high doses of IL-2 to boost the immune system. Between 5-7% of selected patients receiving IL-2 therapy achieved complete‚ durable remission‚ and the seven-year survival rate was 10%. Steven A. Rosenberg‚ MD‚ PhD‚ chief of the surgery branch and tumor immunology division at the NCI‚ is continuing to study the impact IL-2 has against melanoma‚ comparing chemotherapy against IL-2 combined with selected vaccines.

For patients with metastases in the liver‚ doctors at UPCI have been studying the effects of supplementing IL-2 therapy with histamine (a compound released during allergic reactions)‚ an approach based on information that cancer patients with elevated histamine levels seem to fare better in treatment. When Ceplene™‚ a form of histamine‚ was combined with IL-2 for patients with stage IV melanoma with liver metastases‚ their average survival rate almost doubled‚ compared with patients who only received IL-2. The addition of the histamine may boost the body’s ability to generate T-cells in response to the IL-2‚ enabling doctors to administer less IL-2 and maintain treatment longer. Dr. Agarwala is now directing an international phase III trial with this regimen to confirm these initial results.

Biochemotherapy
Doctors at cancer centers across the country are pursuing other avenues to complement existing treatment for patients with metastatic melanoma.
Developed in the 1990s‚ biochemotherapy combines the administration of multiple chemotherapeutic agents and the administration of biological response modifiers such as interferon and IL-2.

Steven J. O’Day‚ MD‚ director of medical oncology research at John Wayne Cancer Institute‚ is studying the optimum way to administer biochemotherapy (usually a regimen of Platinol‚ Velban‚ DTIC‚ interferon‚ and IL-2) to improve the outcome for patients with metastatic melanoma and reduce treatment toxicity. Dr. O’Day’s team has shown positive results for concurrent administration of the drugs with decreasing doses of IL-2. The initial high doses of IL-2 are rapidly tapered‚ which appears to reduce toxicity and improve clinical efficacy.

In a phase II trial with 44 patients who had stage IV melanoma‚ Dr. O’Day’s team reported a 57% response rate; the complete remission rate was 23%; and the median survival rate was 11 to 12 months.

“The response to biochemotherapy is better than chemotherapy alone‚ but the impact on median survival remains marginal to date‚” admits Dr. O’Day. “We have a lot of work to do.”

However‚ Scott Davis’ experience with biochemotherapy gives patients hope.
Davis‚ 59‚ a nationally traveled track and field announcer and director of the Mt. SAC Relays‚ a track meet held every April in Walnut‚ California‚ for 15‚000 athletes from around the world‚ first had a spot of melanoma removed in 1987 from his right calf. It recurred in 1996‚ and doctors removed a lump in his groin. Doctors at John Wayne Cancer Institute started him on immunotherapy with the vaccine Canvaxin™‚ but the tumors reappeared‚ this time in his right hip and thigh. Following a second surgery‚ he started radiation treatment‚ but the tumor in his thigh reappeared. Finally‚ with stage IV melanoma‚ he started biochemotherapy in 1997.

“After the first treatment‚ I felt terrible. I couldn’t control my bodily functions‚ and I asked God to take me after the second treatment. Amazingly‚ after the second treatment‚ the melon-sized tumor in my right leg disappeared. I had four more treatments and took interferon for one year. I’m cured. It’s ironic. In track I’m around so many healthy legs‚ but mine almost killed me.”

Dr. O’Day is currently sponsoring a multi-site clinical study for “maintenance biotherapy‚” one year of immune-stimulating drugs for patients who graduate from biochemotherapy to see if it stops recurrence. “The combination of the two approaches is very promising‚” he says.

New Immunotherapy Approaches
Another approach was announced in September 2002 by Dr. Rosenberg. In the study‚ 13 patients with advanced metastatic melanoma who had not responded to initial treatment were treated with immune cells from their own bodies that had been stimulated in the lab to specifically destroy their tumors. Those cells were reinfused after the patients had received chemotherapy to kill their bodies’ ineffective immune cells and IL-2 to create a hospitable environment for the new lab-powered T cells. Known as “adoptive transfer‚” the technique resulted in at least 50% tumor shrinkage in six of the patients‚ with no growth or appearance of new tumors.

Vaccines are also being tested against melanoma. One of the most promising‚ Canvaxin‚ produced by CancerVax Corp.‚ Carlsbad‚ California‚ is in phase III trials at numerous sites and was given fast-track designation by the U.S. Food and Drug Administration in January 2003 shortly after the results of two trials that showed increased overall survival for both stage III and stage IV (metastatic) melanoma.

Results from nonrandomized phase II clinical trials showed that selected patients with stage III and stage IV melanoma had twice the overall median survival rate when they were treated with surgery plus Canvaxin versus surgery alone or surgery plus chemotherapy. For example‚ patients with stage III melanoma treated with Canvaxin had an overall median survival of 58 months‚ compared with 28 months for earlier patients who only had surgery to remove metastatic tumors in the regional lymph nodes.

Stage IV patients who had undergone surgery to remove all clinically detectable melanoma before receiving Canvaxin had a 40% survival at five years compared to 15% for those who had surgery alone. Although encouraging‚ it is important these data be confirmed in larger phase III trials.

“Unlike therapy with interferon and IL-2‚ vaccine therapy is designed to stimulate a specific response by targeting specific antigens found on cancer cells‚” says Dr. Morton‚ who developed the vaccine in 1984. “Another plus for vaccine therapy is that there are few side effects for patients.”

Keeping the Immune System Turned On
Once doctors succeed in activating the immune system to attack cancer cells‚ the challenge is keeping the immune system on. T cells are the chief aggressors in the immune system‚ but a T cell only stays activated for about three days. Then it stimulates the production of a molecule called CTLA4 on the T cell’s surface. When CTLA4 binds with molecule B7‚ which resides on the surface of another immune cell that fights infections‚ it slams the brake on the immune system response. Medarex Inc.‚ Princeton‚ New Jersey‚ has created a human antibody to CTLA4 that blocks the receptors on CTLA4 and prevents it from binding with B7. Thomas Davis‚ MD‚ NCI‚ Bethesda‚ Maryland‚ is monitoring phase II trials at various sites across the United States.

“The antibody could potentially treat anyone with cancer‚ but we’re currently concentrating on patients with melanoma‚ since it seems to be one of the most immunologically sensitive cancers. Some of the patients receiving only one infusion of the drug have experienced significant shrinkage in tumor mass and relief from symptoms‚” says Dr. Davis.

His team is beginning clinical studies to measure the effects of combining the CTLA4 monoclonal antibody with selected chemotherapeutic agents such as dacarbazine and several tumor vaccines.

Finding Hope
“From all of these studies‚ the only conclusion is that perhaps some combination of these efforts will one day enable doctors to win the war against melanoma‚” says Dr. Kirkwood‚ adding that‚ while the small‚ pilot trials are sources of hope‚ they are not providing many answers.

“Until we do controlled‚ randomized trials to assess the substance of these efforts‚ we don’t know if they will have a meaningful impact on survival‚” Dr. Kirkwood says. “No treatment that’s been properly evaluated has ever shown a significant benefit upon survival in advanced disease. To achieve more progress‚ medical researchers have to move beyond pilot trials and sponsor larger trials.”