Nonsurgical Treatment of Non-Melanoma Skin Cancers

There are many procedural treatments that we have worked on finessing in dermatology, but for some patients with non-melanoma skin cancer, nonsurgical treatments should be discussed. We had the opportunity to review the strengths and weaknesses of nonsurgical treatment approaches for non-melanoma skin cancer and review the indications and future implications of these treatments at ODAC 2023 with Dr. Vishal A. Patel, Mohs surgeon and Associate Professor of Dermatology and Oncology at George Washington University.

Did you know? Skin cancer is more common than all other cancers combined with the incidence rising faster than that of any other cancer.

In the United states, more than 9000 people are diagnosed with skin cancer every day, while more than 2 people die of the disease every hour. At least 1 in 5 Americans will develop skin cancer by the age of 70, and even the financial cost is overwhelming! More than $8 billion is spent treating skin cancers in the United states annually, of which almost $5 billion is for non-melanoma skin cancers. Therefore, understanding primary prevention, secondary prevention, and tertiary prevention is essential to manage these malignancies.

Primary Prevention

Primary prevention is our first form of nonsurgical management for non-melanoma skin cancer. In this, we try to prevent the onset of skin cancer. The main agent studied for primary prevention discussed was nicotinamide.

Nicotinamide

Nicotinamide is a form of vitamin B3, which has been used previously for its anti-inflammatory effects at pharmacologic doses for blistering diseases. Oral nicotinamide has been shown to be effective to reduce actinic damage. Patients receiving it showed a 23% relative rate reduction in new non-melanoma skin cancers compared to placebo. Actinic keratosis followed the same trend, with significant relative reductions observed after the use of nicotinamide. It has even been shown to provide broad-spectrum protection against ultraviolet radiation-induced immunosuppression in humans.

Here are some important fast facts to know about prescribing nicotinamide:

• • Indication: Actinic keratosis
  • Dosing: nicotinamide 500mg twice daily
  • Treatment Timing: Continuous

Three key takeaways you must know about nicotinamide for your next patient visit are as follows:

1. 1. Nicotinamide is likely more effective at reducing relative rates of superficial basal cell carcinoma compared to other basal cell carcinoma subtypes.
   2. It had no difference in reducing squamous cell carcinoma in situ versus invasive squamous cell carcinoma.
   3. Patients with >5 non-melanoma skin cancers in the last 5 years responded more effectively to the nicotinamide than patients with <6 cancers in the previous 5 years.

Secondary Prevention

Secondary prevention involves trying to detect the cancer early and prevent it from getting worse. This is especially important when we think about the development of squamous cell carcinoma from actinic keratosis. This risk is reported in widely variable figures, ranging from 0.01% to 10% over 10 years. Unfortunately, it is not possible to predict which lesions will go on to become squamous cell carcinoma, but the majority of squamous cell carcinoma does arise from precursor actinic keratosis lesions. For these, there are options for management.

5-Fluorouracil

5-fluorouracil is a pyrimidine analog that inhibits thymidylate synthase, blocking synthesis of the pyrimidine thymidylate, the scarcity of which preferentially impacts cancerous cells. 5-FU cream is FDA-approved to treat actinic keratosis and superficial basal cell carcinoma, but it is also often used in an off-label fashion for squamous cell carcinoma in situ, disseminated superficial actinic porokeratosis, and condyloma.

Calcipotriol

Calcipotriol is a variant of vitamin D that is an FDA-approved drug for psoriasis. The exact mechanism is not completely understood, but it is presumed to be an activator in keratinocytes that can trigger an inflammatory response. This response, the result of upregulation of thymic stromal lymphopoietin, establishes an antitumor immunity that blocks skin cancer development in the skin.

Clinical Tip: A 1:1 combination of 5% 5-FU and 0.005% calcipotriene should be used twice daily for 5-7 days for actinic keratosis treatment.

Imiquimod

Imiquimod facilitates a local and acquired immune response by interacting with toll-like receptor 7, found on dendritic cells. This leads to macrophage and neutrophil chemotaxis and T-cell recruitment. It is FDA-approved for the treatment of actinic keratosis, with 5% cream used 2 times weekly for 4 months. When used for superficial basal cell carcinoma, it is FDA-approved to be used 5 times weekly for 6 weeks with a 1 cm margin around the lesion.

Tertiary Prevention

Tertiary prevention is to try to improve the quality of life and reduce symptoms of the cancer that a patient already has. For some patients, such as those with locally-advanced and metastatic basal or squamous cell carcinoma, surgery may not be an option. For these patients, there are medications that interact with the myriad oncologic pathways that lead to cancer proliferation.

Vismodegib

Vismodegib is the prototypic hedgehog pathway inhibitor. Its indications are for metastatic or locally-advanced basal cell carcinoma that has occurred following surgery or in those who are not candidates for surgery or radiation therapy. Dosed at 150mg daily, it is favored over other medications in the same class (e.g., sonidegib) in clinical practice.

Major side effects for this medication can include:

• • Muscle or joint pain
  • Loss of taste and resulting weight loss
  • Hair loss

PD-1 Inhibitor

The discovery of immunotherapy, like cemiplimab or pembrolizumab, provided another agent that is indicated for locally-advanced, recurrent, or metastatic disease if curative radiation therapy or surgery is not feasible. These medications take advantage of immune checkpoint inhibition to reduce the cancer’s burden. However, there are a variety of immune-related adverse events that occur within weeks to months after initiation of these immune checkpoint inhibitors. The list of dermatologic adverse effects are broad, and systemic effects as well involve nearly every organ system potentially.

Summary

There are many meaningful nonsurgical approaches to managing non-melanoma skin cancer. Here are 4 key takeaways to consider in treating these cancers:

1. 1. Anti-PD-1 immunotherapy has changed the way we manage locally-advanced and metastatic cutaneous squamous cell carcinoma.
   2. Cutaneous squamous cell carcinoma is multifaceted and does not live in a silo, which means it may require coordinated multidisciplinary care for optimal outcomes.
   3. New questions are emerging on how to think about the approach to high-risk and locally-advanced cutaneous squamous cell carcinoma.
   4. We need to push the envelope further to better understand and manage cutaneous squamous cell carcinoma.

This information was presented by Dr. Vishal A. Patel during the 2023 ODAC Dermatology, Aesthetic and Surgical Conference.  The above highlights from his lecture were written and compiled by Dr. Nishad Sathe.