New and Ongoing Research in The Field of Skin Cancer

The prevalence of skin cancer, a leading cause of death around the world, is increasing at an exponential rate. Therefore, researchers are persistently striving to evolve and find innovative diagnostic strategies and promising treatments for this potentially fatal condition. Further advancements in this field may give rise to simpler tools for the diagnosis of skin lesions making invasive biopsy techniques unnecessary while also developing novel treatment options that have minimal adverse effects.

Diagnosis of Skin Cancer

Dermoscopy

Dermoscopy, developed in 1987, has become the gold standard as a preliminary diagnostic tool for skin cancer. Once a skin lesion is flagged as possessing malignant potential, a skin biopsy is performed as a confirmatory test. The biopsy is usually performed in an outpatient setting taking less than 20 minutes of the patient’s life.  

More recently, advances in the field of dermatology have rolled out newer modalities to diagnose skin lesions without the need for a skin biopsy. These techniques have been termed as optical biopsies and include optical coherence tomography (OCT) and reflectance confocal microscopy (RCM).

Reflectance confocal microscopy

Reflectance confocal microscopy is a noninvasive technique developed in 2001 that provides imaging of the skin all the way from the epidermis to papillary dermis (depth of 300 micrometers) at a resolution of 1 micrometer. Prior research has demonstrated outstanding success and accuracy with the detection of both melanoma and non-melanoma skin cancers.

According to a meta-analysis, RCM had a sensitivity of 92.7% and specificity of 78.3% for detecting melanoma, while its sensitivity and specificity for detecting basal cell carcinoma was 91.7% and 91.3% respectively. Other studies have also supported the use of RCM in the diagnosis of basal cell carcinoma.

Moreover, researchers observed that RCM performed exceptionally well compared to skin biopsy for pigmented melanomas (structureless lesions). Additionally the study reported combined RCM and skin biopsy as being significantly superior in diagnosing skin lesions in comparison to skin biopsy alone as the combination assessment had a relatively higher reduction in the number needed to treat (NNT) ratio.

Optical coherence tomography

Optical coherence tomography is an imaging technique developed in 2015 that uses infrared light to magnify the surface of the skin lesion. This device allows examination of skin at a resolution of roughly 10 micrometers and produces axial images at a depth of 2mm to the reticular dermis and mostly used to diagnose non-melanoma cancers such as basal and squamous cell carcinoma. Moreover, efforts are also being directed toward the diagnosis of melanoma skin cancers using a variant of OCT known as speckle-variance OCT. Multiple systematic reviews have demonstrated variable success in the diagnosis of basal cell carcinoma via OCT while reporting higher success rates reported in differentiating abnormal skin cells from healthy ones.

Ongoing Research on Treatment of Skin Cancer

Conventional treatments of skin cancer include surgery, chemotherapy, and radiation. But, more recently skin cancers have been found to respond better when treated with combination drug therapies.

Currently, there are a variety of treatments ranging from surgical to non-surgical options. Novel non-surgical treatments such as photodynamic therapy, laser surgery, and topical drugs have shown efficacy in improving survival outcomes and providing patients with little to no side effects compared to other options.

FDA Approved Drugs

There is a wide range of drugs approved by the Food and Drug Administration (FDA) to choose from with varying efficacy depending on skin cancer type. Based on the flowchart below, within the past five years, you can see the continuous evolution of different classes of drugs that are approved by the FDA for various types of skin cancers. Immunotherapy and targeted therapy are currently the modalities of choice for treating melanoma and other skin cancers, but even these treatments are constantly evolving as researchers look for safer drugs with higher efficacy.

Areas of research and continuous development

1) Laser-based treatment

In July of 2019, researchers developed the Cytophone, which is a device that can both detect and kill melanoma cells in the blood. The Cytophone uses laser light and sound to not only detect the melanoma cells but also to destroy them. A recent study conducted by Galanzha and colleagues has demonstrated the Cytophone’s ability to detect cancer cells in 27 out of 28 individuals while simultaneously reducing the number of cancerous cells by killing them with its synergetic diagnostic and therapeutic action. Larger scale studies are needed to further illustrate the cytophone’s efficacy to warrant its application in patients.

2) Photodynamic therapy

Photodynamic therapy (PDT), first introduced in the 1900s, is a treatment that relies on light to destroy cancer cells. Photosensitizer molecules are illuminated by the light to generate reactive oxygen species (ROS), which destroys cell membranes and subsequently leads to cell death. ALA and MAL are some of the most frequent agents that are used in combination with PDT.

Previous studies have demonstrated superiority in ALA/PDT compared to vehicle/PDT, complete response rates of actinic keratoses (AK) for ALA/PDT ranged from 17% to 30% at week 12, compared with 2% of the vehicle/PDT group. For the treatment of nodular BCC, MAL/PDT has exhibited better success compared to ALA/PDT treatment.

A meta-analysis by Zhu et al. exhibited that PDT is of similar efficacy to surgical removal for treatment of BCC, but which came at a cost of increased risk of recurrence. A recent prospective study compared LED–PDT to Pulsed Dye Laser (PDL)-PDT for the treatment of AKs for a period of 12 months. Researchers demonstrated no significant difference between both groups with regards to the difference in the amount of AKs, suggesting that PDL-PDT can also be an effective treatment for actinic keratoses.

3) Cryotherapy

Cryotherapy, discovered in 1945, is the process of destroying a skin lesion by freezing it with liquid nitrogen. Liquid nitrogen is applied to the lesion using a cotton applicator stick or an aerosol spray.

A study by Holt evaluated the outcomes of cryotherapy in skin cancer over a period of 5 years. Holt demonstrated a 97% cure rate with a recurrence rate of under 3% for all types of skin cancers, including (basal cell carcinomas, squamous cell carcinomas, and Bowen’s tumors). Therefore, cryotherapy has demonstrated success in the treatment of non-melanoma skin cancer.

There have been varying results regarding the efficacy of cryotherapy compared to other treatment options. For example, a study demonstrated that response rates were higher in the PDT group (91%) compared to the cryotherapy group (68%) in patients with actinic keratoses.

In comparison, a meta-analysis conducted by Mpourazanis in June of 2020 compared the efficacy of photodynamic therapy to cryotherapy in patients with basal cell carcinomas. Mpourazanis and colleagues demonstrated no significant difference in cure and recurrence rate between both therapies suggesting they both yield similar effects.

4) Topical drugs

Topical creams applied to the skin directly are another option for non-surgical treatment. These drugs are usually used for the treatment of non-melanoma skin cancers such as basal cell carcinoma and actinic keratoses. The two most common drugs are 5-fluorouracil and Imiquimod.

5-fluorouracil

5-Fluorouracil (5-FU) is a topical drug, known as a fluorinated pyrimidine, which interferes with DNA synthesis by blocking the mechanism of converting deoxyuridylic acid to thymidylic acid which contributes to cell death. 5-FU is an FDA-approved treatment for superficial basal cell carcinoma but has been used off-label for the treatment of squamous cell carcinoma.

A randomized controlled trial in 13 patients showed a 90% complete response rate treated with 5% 5-FU twice daily for two weeks. Similarly, another study demonstrated a 90% complete response rate in patients treated with 5-FU twice daily for twelve weeks. With regards to efficacy, a randomized study compared 5-fluorouracil to MAL photodynamic therapy of which reported similar response rates. Many studies have demonstrated 5-fluorouracil to be safe and produce good cosmetic outcomes.

Imiquimod

Imiquimod 5% is a topical Toll-like receptor 7 agonist that produces cytokines to help increase T cell immunity. The FDA has approved this treatment for the treatment of superficial and nodular basal cell carcinoma. A study by Vidal and colleagues published in JAMA dermatology evaluated the outcomes of the use of topical Imiquimod for the treatment of basal cell carcinoma for five years. Results revealed a complete response rate in 65% of all basal cell carcinomas regardless of type. When stratified, superficial BCC had the best rate of 100%, modular BCCs had a 75% response rate, and infiltrate BCC only had a 60% response rate.

Furthermore, when Imiquimod was compared to surgical removal of the tumor, a randomized study demonstrated a higher five-year success rate for the surgical cohort (97.7%) compared to the imiquimod group (82.5%). Therefore, it is vital that researchers attempt to investigate how to increase the efficacy of Imiquimod with the possibility of using it in combination therapy with other treatment options.

In conclusion, skin cancer research is an ongoing field that continues to change and adapt based on the latest innovations and research findings. Researchers hope that within the next decade, novel diagnostic methods and interventions will emerge that can genuinely affect the methodologies by which skin cancer is diagnosed and treated. .

References

Galanzha EI, Menyaev YA, Yadem AC, et al. In vivo liquid biopsy using Cytophone platform for photoacoustic detection of circulating tumor cells in patients with melanoma [published correction appears in Sci Transl Med. 2019 Sep 18;11(510):]. Sci Transl Med. 2019;11(496):eaat5857.

Bath-Hextall F, Ozolins M, Armstrong SJ, et al. Surgical excision versus imiquimod 5% cream for nodular and superficial basal-cell carcinoma (SINS): a multicentre, non-inferiority, randomised controlled trial. Lancet Oncol. 2014;15(1):96-105.

Zhao B, He YY. Recent advances in the prevention and treatment of skin cancer using photodynamic therapy. Expert Rev Anticancer Ther. 2010;10(11):1797-1809.

Mpourazanis, G, Mpourazanis, P, Stogiannidis, G, Ntritsos, G. The effectiveness of photodynamic therapy and cryotherapy on patients with basal cell carcinoma: A systematic review and meta‐analysis. Dermatologic Therapy. 2020;e13881.

Ahlgrimm-Siess V, Laimer M, Rabinovitz HS, et al. Confocal Microscopy in Skin Cancer. Curr Dermatol Rep. 2018;7(2):105-118.