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New Treatments for Melanoma

Melanoma is the most rapidly growing cancer in this country, except for prostate cancer and certain subtypes of gastric cancer. About 1:70 individuals in this country will have a chance of developing melanoma. That incidence has gone up dramatically. The death rate has not changed so dramatically and I think the cynic might say that we are picking up earlier lesions.

Regardless of the genetic status of the patient, we recommend that they have close follow-up, that their family members be screened by a dermatologist, not genetically, because we know that families that go to the beach together get melanoma together, whether or not it’s inherited.

Cutaneous melanoma. There are four major types and one minor type of cutaneous melanoma. Superficial spreading melanoma, nodular, acral-lentiginous, lentigo maligna and desmoplastic. Desmoplastic being the rare type. Superficial melanoma accounts for about 70% of the melanomas we see. It typically occurs in a precursor lesion about 50% of the time. The latency period before it develops what is called a vertical growth phase histopathologically can often be two years.

Nodular melanoma. Nodular melanomas are similar to superficial spreading melanomas, probably account for about 15% of the melanomas that we see and often don’t have a long latent period. And that is, they arise essentially with a vertical growth phase and that is why they grow out. This picture also illustrates another phenomenon we see, which is a halo.

Lentiginous melanoma often occurs on the soles of the feet, the palms of the hands, subungually. It’s important in patients who have a history of melanoma to examine between their toes, because a lesion can arise. It often occurs subungually, typically under a fingernail or toenail.

Staging melanoma. There are two staging systems. One is the Clark’s level, which is falling into disuse, and the second is Breslow’s technique. Clarks’ technique simply gives an anatomic designation to the level of invasion of the deepest malignant melanocyte. From level 5 into the subcutaneous fat, level 4 into the reticular dermis, level 3 into the papillary dermis.

Therapy. Micro-staging is an important predictor of the local recurrence rate, and it dictates the kind of local surgical therapy we provide to the patient. Thin lesions, less than 0.76, have a very low local recurrence rate even regardless of margin. Whereas thick lesions have a much higher local recurrence rate. And of course a local recurrence is simply tumor that is left behind, probably micrometastic tumor.

Regional lymph nodes. Surgeons have long understood that the thickness of the lesion on the lower axis also correlates with regional and distant metastases. For very thin lesions, Ia lesions, there is a 2-3% chance of distant metastases and a 2-3% chance of regional metastases. For thick stage IIb lesions, the potential for metastases in both regional and distant distributions is roughly equivalent. But for intermediate thickness melanomas, between 0.76 and 4 mm.

One of the trials had an interesting finding. This is the outcome of WHO trial 14. It was published about two years ago. And what it shows is in the patients who never developed lymph node metastases, either at the time of operation or at the time of observation following, there is obviously no difference in outcome because they never developed lymph node metastases. But for the two groups of patients who developed lymph node metastases.

Elective lymph node dissection. In 1991 Don Morton published his seminal work on sentinel lymph node biopsy that came from his initial studies in patients with extremity and truncal melanoma. The hypothesis behind the sentinel lymph node biopsy that’s so widely used now in melanoma, and has crept into breast cancer diagnosis and therapy, colon cancers and other surgeries as well, is as follows: the idea is that an individual lesion has a defined pattern.

The data are relatively consistent. In most cases about 15% of patients have positive sentinel lymph nodes, and in most cases about two-thirds, the only positive is in the sentinel lymph node. Typically, the sequence of events is: make the diagnosis of melanoma.

Locally recurrent disease. This is probably the most difficult problem we have in melanoma. These are called in-transit melanoma metastases. This is a woman who had a primary on her foot, she had a sentinel lymph node biopsy and then removal of her proximal groin lymph nodes, and she subsequently developed multiple small, what are called satellite lesions in the skin. These are called in-transit metastases. They cannot be surgically removed.

Adjuvant therapy. The vast majority of patients present with relatively thin melanomas, but about 6% of patients present with stage III disease or metastatic disease at the time of presentation. Another 12% are unknown, so probably about 10% of patients actually present with stage III or stage IV disease. Clearly prognosis has a lot to do with the thickness of the lesions, and for patients with stage III disease, it has a lot to do with the number of involved lymph nodes, as is true for breast cancer, for example.

The question is: do we have agents that we can treat them with when they are micro-metastatic? Chemotherapy has been tried. I am not going to go through this in detail here. Chemotherapy has been tried to the point where bone marrow transplant has been used, autologously supported, to treat patients with high risk, multiple positive lymph nodes.

There were 31 patients in this trial who had IIb disease and this is the interferon arm here, and this is the observation arm. There is no difference here statistically. But because the entry criteria of the trial included these patients, the FDA approved interferon therapy for the IIb lesions. Because of this approval the staging groups changed T4 N0 disease to be stage III.

Now what about interferon use in stage II patients? Because of the promising results in the trials, it has been looked at twice in a randomized setting. For Hamberger in JCO and Grove in Lancet last year, both looked at a relatively moderate number of patients who had clinical stage II, not surgically staged stage II patients, and treated them with interferon at the time of the diagnosis. Both suggested a small disease-free survival advantage, but the criticism of this trial is as follows: both of these patient populations were not surgically staged.

Metastatic disease. Melanoma is a embryonically migratory cell. It can go anywhere. PET scan seems to have a somewhat improved sensitivity in melanoma, compared to other diseases. For one reason or another melanoma appears to have an enhanced metabolism.

The other technique that is coming to the fore in melanoma is the use of reverse transcriptase PCR, or RTPCR, to try to identify evidence of circulating melanoma cells either in peripheral blood or in sentinel lymph node biopsied lymph nodes.

Chemotherapy for melanoma. Response rates, 25% for the best agent which is the carbazine, which is the only FDA approved chemotherapy agent. The carbazine has never been shown to affect the survival of a melanoma patient despite this response rate. Others have been used, BCNU, CCNU, other nitrosoureas, transplants have been done. A similar story to the isolated limb perfusion. High response rates, very short duration of response.