Imiquimod battles melanoma in situ and more

December 31, 2012

Imiquimod shows promise for treating cases of melanoma in situ that aren’t amenable to surgery, and for other off-label indications such as metastatic melanoma, says M. Shane Chapman, M.D.

“For melanoma in situ, the gold standard is surgical excision, regardless of where it’s located. But often on the face and in other difficult locations such as near the eyelids and oral mucosa, we may opt not to do that,” says Dr. Chapman, section chief of dermatology at Dartmouth-Hitchcock Medical Center, Lebanon, N.H.

Reasons that one might eschew surgery in cases of melanoma in situ could include advanced patient age, overall poor health or large tumor surface area, Dr. Chapman says. “However, for deeper lesions and nodular melanomas, surgical excision is the best option.”

Nevertheless, he says that increasingly, patients ask him about nonsurgical options. “Patients get online. They read everything out there, and they know there are other options, even though they don’t know if they work well or not,” he explains.

Imiquimod option

Regarding the role of imiquimod with melanoma in situ, because there are no strong studies in this area, physicians don’t know what to tell patients about imiquimod’s clearance rate, Dr. Chapman says.

Dr. Chapman

Additionally, “Nobody owns the drug anymore - at least not the 5 percent concentration. Therefore, there won’t be much industry-sponsored financial help for us to figure out what’s the best dosing regimen and what the clearance rate is.” He tells patients that based on existing reports, imiquimod’s cure rate for melanoma in situ ranges between 50 and 90 percent if used for 12 weeks, preceded by a retinoid.

The 90 percent figure comes from a 28-patient study in which imiquimod treatment cleared 26 of 28 patients with lentigo maligna (LM; Naylor MF, Crowson N, Kuwahara R, et al. Br J Dermatol. 2003;149(Suppl s66):66-69). Dr. Chapman says, however, these researchers followed patients for only one year post-treatment.

In contrast, “Imiquimod doesn’t work for everybody,” he says. One patient that Dr. Chapman treated for a large scalp lesion initially cleared but returned eight months later with “a bright red nodule in the center of his imiquimod-treated LM. It was an amelanotic nodular melanoma, which we excised.” The melanoma has recurred twice since then, and was surgically excised both times, he adds.

“The fact that the tumor recurred as an amelanotic lesion begs the question: were there two different melanocyte or melanoma cell types there? It came right back where the biopsy was taken. Did the biopsy change the tissue milieu there? I don’t know,” he says. “But the patient is doing well for now. Seven years out, he’s had no other recurrences.”

In retrospect, “We probably should have done surgical excision,” Dr. Chapman says. “Even though it may look clinically like someone is clear, the patient may not be disease-free.”

Such was the case in a series of 44 patients given imiquimod before surgical excision of LM. In this study, based upon clinical examination after imiquimod treatment, “It looked as though 33 patients were clear,” Dr. Chapman says. “But when investigators excised the lesions for histologic examination, they missed three with remaining disease histologically (Cotter MA, McKenna JK, Bowen GM. Dermatol Surg. 2008;34(2):147-151. Epub 2007 Dec 17).”

Dr. Chapman says that a colleague in New Hampshire used three to four months of imiquimod treatment for a homeless patient who had a large melanoma in situ lesion located on the right cheek, but no lymphadenopathy. She was disease-free for two years thereafter, he says, but then she died of a heart attack.

“I’m not saying that she would not have had a recurrence later on, but beyond treating the tumor itself, the more fascinating thing is, what is going on here and how can we incorporate that for some of our distant metastatic patients, or patients with local metastases?” Dr. Chapman says.

One patient Dr. Chapman treated was a 36-year-old man with more than 200 cutaneous metastases. “We bathed him in imiquimod, and we started to see his melanoma metastases disappear,” he says. “He is now 42 years old and doing well. I don’t know how or why this worked in this particular patient, but it did.”

While the topic remains controversial, “I believe there are some difficult surgical cases, in terms of tumor size, location or functional deformity resulting from surgical procedures, where imiquimod could be appropriate,” he says, adding that many published cases have involved difficult melanoma and melanoma in situ lesions in which surgery was not a realistic option or had failed.

Additionally, “Some patients prefer to try imiquimod or some other nonsurgical therapies first,” he explains. In Dr. Chapman’s practice, 1 to 5 percent of his patients with melanoma in situ use imiquimod in some manner.

Some surgeons prescribe topical imiquimod or a retinoid (particularly for patients with significant sun damage in the treatment area) for use after surgical excision as well. “We still don’t have a 100 percent clearance rate with any surgical procedure,” including Mohs surgery, Dr. Chapman says. On the whole, five-year recurrence rates for imiquimod for melanoma in situ range from 5 percent up to 20 percent. However, he adds, “I don’t believe five years is enough. I see patients who are five years out and they’re still having recurrence of their melanoma in situ. I want to see 10-year data.”

One compelling reason to consider imiquimod and other toll-like receptor (TLR) agonists for melanoma in situ is the fact that imiquimod works, to a degree, Dr. Chapman says. Imiquimod is a TLR7 agonist. Natural TLR7 agonists include the influenza virus and HIV. “If you think about it, the flu-like symptoms one can get with imiquimod are similar to those of other viral diseases,” he says.

Typically, Dr. Chapman has his patients pretreat with a retinoid (preferably tazarotene) for two weeks, making them more sensitive to imiquimod. Then patients apply imiquimod five times weekly for 12 weeks. “We’ve gone out to 16 weeks and gotten no better results,” he says, adding that patients use weekends as drug holidays.

“Sometimes these patients are colonized with Staphylococcus aureus. You really don’t have to treat it, but you can. Then I always try to get a post-treatment biopsy, or two or three. We follow these patients very closely, just as we would a surgical patient, with serial examinations and a Woods lamp,” he says. DT

 

Disclosures: Dr. Chapman has performed clinical research for 3M/Graceway, previous owners of imiquimod.