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Nonmelanoma skin cancer (NMSC), primarily comprising basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), continues to rise in the United States,1,2 and recent studies explore the array of treatment options, particularly those of a nonsurgical nature.

“Skin cancer is a continually rising epidemic in our country and [is] a large expense for our health care system,” said Vishal Patel, MD, assistant professor of dermatology at the George Washington University School of Medicine and Health Sciences in Washington, DC, in an interview with Practical Dermatology magazine. “We need to consider all types of therapies to find the best and most cost-effective treatment for each patient and each tumor type,” he said. Dr. Patel served as corresponding author on a recent review of topical treatments of cutaneous malignancies.

“There have been many advancements in the treatment of skin cancers recently, so it was timely to do a review of the current literature to help clinicians consider nonsurgical treatments that might benefit their patients,” he said.

In the review, published in the American Journal of Clinical Dermatology, Dr. Patel and colleagues identified studies of BCC, cutaneous squamous cell carcinoma (CSCC), in situ melanoma (MIS), and extramammary Paget’s disease (EMPD).3

SUCCESS VARIES

Overall, the researchers found complete clearance rates ranging from 90% to between 90% and 93% for 5% 5-fluorouracil and from 71% to 76% for imiquimod in treating patients with superficial BCC. For those with nodular BCC, clearance rates were 91% at 3 months with photodynamic therapy (PDT); sustained lesion clearance responses were 76% after a follow-up of 5 years. Patients with nodular BCC had clearance rates of 53% to 76% with imiquimod.

Among patients with SCC in situ, clearance rates ranged from 52% to 98% for PDT, from 67% to 92% for fluorouracil, and from 75% to 93% for imiquimod. Clearance for MIS rates ranged from 53% to 92% for imiquimod. In cohort studies and case series of patients with EMPD, 54% of 110 patients showed a clinical complete response with imiquimod.

CONSIDER THE RANGE OF TOPICAL OPTIONS

Dr. Patel said he was not particularly surprised by the findings from the studies included in the review. However, “we were surprised at the number of case reports of topical treatments that have been tried in off-label indications for rare and atypical skin cancers,” he told Practical Dermatology magazine.

“It is important to understand the efficacy and data of the various topical treatments to fully discuss them with patients,” Dr. Patel emphasized.

He also noted that clinicians should conduct a risk assessment of any tumors and communicate that risk to patients. Then, consider the efficacy of topical treatments and whether this is amenable to the patient as an option, he explained. “Topical treatments may not have as high cure rates as surgery, but they may be superior to surgery in many cases when considering all the factors that may potentially impact a patient,” he said. The pros and cons need to be completely understood and discussed between the clinician and patient, he added.

Persistent barriers to successful topical treatment of NMSC include patient confusion over the range of available treatments, difficulty with application to certain areas, and the lack of availability of certain formulations from a regular pharmacy, Dr. Patel said. “Discussing options to select the right treatment for the right patient can help overcome these potential barriers,” he said.

Looking ahead, “There is a lot of excitement around topical fluorouracil and calcipotriene,” said Dr. Patel. “However, we need to perform a larger scale multi-center, randomized study to validate these results, which will hopefully lead to an FDA approval of this medication for actinic keratosis and thin skin cancers, including superficial BCC and SCC in situ,” he said.

POTENTIAL OF PDT

In addition to topical therapy, PDT continues to gain popularity as a nonsurgical treatment option for skin cancer. However, a review of the current directions in development was needed to support next steps, according to a team of researchers from China.

In a review published in Clinical, Cosmetic and Investigational Dermatology, Jiachen Sun, PhD, and colleagues identified 2,662 publications from around the world published between 1988 and 2022.4 They assessed the pros and cons of PDT for skin cancer. Their key pros included the ability to be selective and specific in treatment, reducing unnecessary cytotoxicity and damage to other parts of the body.

The drawbacks of PDT included variation in skin parts, types, and colors that may affect patient responses to aspects of PDT including absorption, or different parts of the same patient, which may challenge a dermatologist’s skills and expertise, they wrote. Other potential downsides included patient side effects of tingling, burning, or localized redness, swelling at the area of treatment, and the relatively high cost, they added.

The ideal PDT photosensitizer, according to the researchers, “should have a relatively single and stable component, with a good absorption peak for the 600 to 900 nm light source.” Combining PDT with other treatments, such as CO2 ablative fractional laser (AFL)-assisted PDT, has demonstrated lower recurrence and improved cosmetic results for patients with BCC, they said.

HOW PDT STACKS UP

Data comparing the efficacy of PDT with other treatment modalities are, however, limited, according to an international team of researchers led by Yun Ou-Yang, MD, of Guangzhou Medical University in China. Existing treatments for NMSC, while effective, often lack specificity and are associated with high levels of adverse events and undesirable cosmetic results, and PDT represents a safe alternative that merits further exploration, they wrote.

In a systematic review and meta-analysis published in Frontiers in Medicine, Yang and colleagues identified 17 randomized controlled trials from 21 publications that included comparisons of PDT with each other and with surgery, placebo, cryotherapy, imiquimod, or fluorouracil.5 The most common photosensitizing agent was methyl aminolevulinic acid (MAL), but some studies included 5-aminolevulinic acid (5-ALA).

The study population included 2,166 individuals. A total of 12 studies involved patients with BCCs, and five involved patients with SCCs. The mean age of the study participants was 67.3 years, and approximately half were female. All studies reported on treatment response at 3 months, while some had longer follow-up periods. MAL-PDT was significantly superior to placebo in two studies in terms of clinical response. However, MAL-PDT was significantly less effective than surgery and YAG-AFL-PDT.

In a meta-analysis, YAG-AFL-PDT “may be superior to MAL-PDT for response and recurrence, without compromising on cosmetic outcomes or risk of adverse events,” but larger studies are needed to confirm this result, the researchers wrote.

Recurrence rates among treatments were generally similar at 12 months. At a longer follow-up of 24 to 60 months, more lesions recurred after PDT compared with surgery and imiquimod, and PDT was associated with more adverse events and pain. However, PDT came out ahead on cosmetic appearance, and was more likely than surgery or cryotherapy to be rated as “good” or “excellent,” the researchers noted.

The review by Yang and colleagues was limited by the small number of studies, but the results highlight the need to consider patient preferences on treatment for any particular NMSC lesion.

Dr. Patel had no relevant financial conflicts to disclose.

The researchers on the PDT studies had no financial conflicts to disclose.

1. Garrido PM, Borges-Costa J. Hydrochlorothiazide treatment and risk of non-melanoma skin cancer: review of the literature. Rev Port Cardiol (Engl Ed). 2020;39(3):163-170.

2. Garbutcheon-Singh KB, Veness MJ. The role of radiotherapy in the management of non-melanoma skin cancer. Australas J Dermatol. 2019;60(4):265-272.

3. Algarin YA, Jambusaria-Pahlajani A, Ruiz E, Patel VA. Advances in topical treatments of cutaneous malignancies. Epub 2022 Sep 28. Am J Clin Dermatol. 2023;24(1):69-80. doi: 10.1007/s40257-022-00731-x.

4. Sun J, Zhao H, Fu L, Cui J, Yang Y. Global trends and research progress of photodynamic therapy in skin cancer: a bibliometric analysis and literature review. eCollection 2023. Clin Cosmet Investig Dermatol. 2023;16:479-498. doi: 10.2147/CCID.S401206.

5. Ou-Yang Y, Zheng Y, Mills KE. Photodynamic therapy for skin carcinomas: a systematic review and meta-analysis. Front Med. 2023;10:1089361. doi: 10.3389/fmed.2023.1089361.

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