Neoadjuvant Intralesional 5-Fluorouracil Injection: Improved SCC Treatment in Older Patients

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After entering the patient room, she smiled up at me as she emotionally prepared herself for her third intralesional 5-fluorouracil (5-FU) injection. My patient who was about to turn 80 years old, told me she did not want to spend the end of her life recovering from surgery. She had a history of diabetes, immunosuppression, and blindness in her left eye. She was scared that a squamous cell carcinoma near her right eye was going to take what was left of her limited vision. After discussing the options for treatment, including Mohs surgery with oculoplastic coordination, radiation, and intralesional chemotherapy, we decided together to do neoadjuvant intralesional 5-FU to decrease the size of the tumor and hopefully give her more time to make her final treatment decision. We did a series of intralesional 5-FU injections before she ultimately elected for a procedure to remove the skin cancer.

One of the most common types of cancer, squamous cell carcinoma (SCC), accounts for approximately 20% of all nonmelanoma skin cancers.¹ There is a potential for metastasis if it is left untreated. Although Mohs surgery and surgical excision are the gold standard treatments for SCC, there are other modalities of treatment for when surgery is not the best option. The patient may have significant health comorbidities or an extensive history of skin cancer surgeries that makes them less likely to want to undergo surgery. If a tumor is large, the surgery may cause significant morbidity, including tedious reconstruction. Considering this, we can offer other options of therapy as dermatologists and cutaneous oncologists. Nonsurgical options can be alternative treatments or neoadjuvant to surgery to help decrease the tumor burden before surgery. One of these alternative therapies gaining popularity is intralesional 5-FU chemotherapy. Intralesional 5-FU is a localized, effective therapeutic for patients who elect to delay therapy or are not ideal candidates for surgery or radiation.

Intralesional 5-FU

5-FU is an antimetabolite pyrimidine analog that inhibits DNA synthesis in cells that are rapidly dividing, such as the ones in cancers.² By stopping DNA synthesis, these cells are then forced to undergo apoptosis and necrosis. Also, 5-FU works to rev up the immune system to attack the cancer cells. Lymphocytes and macrophages are recruited to the tumor site. 5-FU has been used historically as a topical or systemic agent for colorectal and head and neck cancers. In dermatology, we can use its intralesional formulation for cutaneous squamous cell carcinomas. As opposed to the topical application of the medication, 5-FU injections deliver a higher drug concentration to the cancer directly and minimize systemic exposure and adverse effects.

Administration of the drug is easy. We directly inject the 5-FU into the location of the SCC with a 30-gauge needle. We vary the dosage and frequency of injections depending on the depth and size of the tumor. We administer intralesional 5-FU at 50 mg/mL concentration with the maximum concentration being 1 mL per encounter. We usually schedule patients for biweekly injections until there is either resolution or decreased size of the tumor. It is difficult to predict the number of sessions that will be needed to treat or shrink a tumor, but patients should expect treatment to take weeks to months.

There are many research studies with results demonstrating the efficacy of intralesional 5-FU for the treatment of patients with SCC. Investigators in a retrospective case series and comprehensive literature review described how 20 of 21 (82.6%) cutaneous SCCs cleared from intralesional 5-FU, and only 1 lesion (4.3%) recurred after injections.³ Four was the average number of treatments required for clearance of tumor with minimal and self-limited adverse effects.³ Investigators in another retrospective study found that 158 of 172 patients (91.9%) had clinical resolution of SCC with treatment of IL5-FU at 4 weeks.⁴ Only 1 (0.63%) patient had a recurrence at the 11-month follow-up.

When to Consider Using Intralesional Fluorouracil (5-FU)

It can be difficult to decide which patients would benefit from intralesional 5-FU. Recently, an 86-year-old woman who used a wheelchair and had dementia came to our office to discuss options for a large, keratoacanthoma-type squamous cell carcinoma on the lower lip. Accompanied by her loved one, she noted that the diagnosis had been a shock because for months she thought the tumor was nothing to worry about. After talking through various treatments, including surgery, radiation, and intralesional 5-FU, the patient and her family decided to pursue intralesional 5-FU, and then if the skin cancer continued to get smaller but persisted, surgery would be considered. However, they wanted to try a nonsurgical approach first because of her other health conditions.

Patient Characteristics for Intralesional 5-FU

We have found that neoadjuvant intralesional 5-FU has been a helpful option for patients with SCC who have the following characteristics:

1) Large tumors

If there are large SCCs in areas where surgery would lead to significant cosmetic or functional impairment, then intralesional 5-FU can be offered neoadjuvantly. This helps make the surgery less morbid and reduces the amount of tissue needed to be removed.

2) Surgical fatigue

Patients who have had numerous surgeries can get surgical fatigue after going through multiple procedures. If a patient has multiple SCCs, then intralesional 5-FU can be offered to reduce tumor burden before considering more surgery. We have found it most beneficial for patients who continuously develop multiple SCCs on the lower legs and have a history of lower leg edema.

3) Older age or comorbidities

For example, I had a patient in a nursing home who had a large SCC on the nose and opted for neoadjuvant intralesional 5-FU to minimize the possibility of requiring a large interpolation flap. Some patients benefit from nonsurgical treatments that are minimally invasive if they have significant comorbidities such as dementia, frailty, etc.

Adverse Effects and Monitoring

One of the first things patients want to know about intralesional 5-FU is whether it will be painful to receive the injection. We always warn patients that there is discomfort and a burning sensation from the needle and the medication, similar to the effects of lidocaine injections. We often try to inject the medication with a smaller needle to minimize discomfort. Patients have reported ongoing discomfort for a while after the injection, which eventually resolves. Overall, intralesional 5-FU is well tolerated by patients because most of the adverse effects are mild and limited to the injection site. Other common self-limiting adverse effects include erythema, swelling, and possible ulceration of the skin. Although rare, there is a small risk of systemic absorption when larger volumes of medication are injected. If that were to happen, patients would report symptoms consistent with bone marrow suppression or gastrointestinal upset after receiving the medication. To avoid this possibility, we limit the maximum amount of 5-FU being injected to 50 mg/1 cc per treatment date.

For patients with SCC who are not good surgical candidates or who are interested in alternative treatments prior to surgery, intralesional 5-FU chemotherapy is an excellent neoadjuvant treatment option to have in the dermatologist’s skin cancer treatment arsenal. This method of administering chemotherapy is minimally invasive, effective, and easy to use in the clinic. It has a great safety profile, can help reduce morbidity from surgery, and is quickly becoming a useful tool for managing SCC both as an alternative and neoadjuvant treatment. For my 80-year-old patient who decided to undergo intralesional 5-FU sessions, she ultimately chose radiation instead of surgery. She felt empowered by the ability to make her own decisions with the knowledge of all her options.

Nicole A. Negbenebor, MD, FAAD, is a Mohs micrographic surgery and cutaneous oncology clinical assistant professor and director of the Skin of Color Clinic in the Department of Dermatology at the University of Iowa in Iowa City.

References

1. Samarasinghe V, Madan V. Nonmelanoma skin cancer. J Cutan Aesthet Surg. 2012;5(1):3-10. doi:10.4103/0974-2077.94323

2. McDonald SM, Neidenbach PJ. Intralesional 5-fluorouracil in the treatment of squamous cell carcinoma in an elderly patient. Cureus. 2024;16(3):e55855. doi:10.7759/cureus.55855

3. Luu W, McRae MY. Intralesional 5-fluorouracil as a management for cutaneous squamous cell carcinomas: a rural Australian retrospective case series. Australas J Dermatol. 2023;64(4):556-559. doi:10.1111/ajd.14148

4. Maxfield L, Shah M, Schwartz C, Tanner LS, Appel J. Intralesional 5-fluorouracil for the treatment of squamous cell carcinomas. J Am Acad Dermatol. 2021;84(6):1696-1697. doi:10.1016/j.jaad.2020.12.049