Squamous cell carcinoma (SCC) of the skin is exceedingly common. For the most part, cutaneous
SCC grows slowly and has a very high cure rate with excision for deep tumors or
mechanical/chemical destruction for superficial tumors. While metastases are uncommon in the
short-term, tumors can be very locally destructive; thus, their timely treatment is
indicated. SCC develops through a stepwise progression from precancerous lesions known as
actinic keratosis (AK)(less than full thickness epidermal involvement), then in-situ SCC
(SCCIS) (full thickness epidermal involvement) and finally invasive SCC (full thickness
epidermal involvement plus invasion/downward growth into the dermis).
For SCCIS, topical treatment with 5-fluorouracil (5-FU) cream (a topical antineoplastic
agent) is an established, off-label treatment offering cure rates that are competitive but
slightly inferior to surgical destruction or excision. The existing regimen requires patients
to apply the medication twice daily for six weeks. The benefits of treatment with topical
5-FU is that the patient can treat a large-diameter lesion with minimal post-treatment
scarring and an excellent cosmetic outcome. Alternatives to topical 5-FU include
electrodessication and curettage (ED&C), an office-based procedure performed under local
anesthetic in 10-15 minutes that includes 3 alternating cycles of curettage and desiccation
with a hyfrecator device; this area is allowed to heal by secondary intention and usually
heals with a broad, circular, hyperpigmented/red scar. The other alternative is wide local
excision (WLE). Both invasive procedures carry some risk of complications, including
infection, bleeding/hematoma formation (only with WLE), and wound dehiscence (only with WLE).
The downside to topical 5-FU treatment is that it causes a temporary cutaneous reaction
characterized by erythema, some burning and tenderness, and even some vesicle formation. This
reaction is expected and reflective of the medication (and ensuing inflammatory reaction)
taking effect, and it is explained to patients prior to starting the medication. This
reaction is tolerable by most patients when used for the 2-3 weeks required to treat AKs, but
it can in some cases become intolerable when patients are required to use the medication for
the full 6 weeks to treat superficial skin cancers. However, the benefit to using the topical
chemotherapeutic agent is that, after healing, the end result is excellent in terms of
cosmesis (no or very little scarring).
While less often used for superficial SCC/SCCIS, topical 5-FU is routinely and ubiquitously
employed in dermatology for treatment of actinic keratosis, which, as previously noted, are
pre-cancerous lesions that ultimately progress to SCCIS. Histologically, AKs appear as
partial thickness cellular atypia of the epidermis. Normally, patients need to treat a given
area twice per day for 2-3 weeks in order to sufficiently treat an area with many AKs. A
study published in 2017 discovered that combining topical calcipotriene 0.005% ointment
(vitamin D analogue) with topical 5-FU 5% cream and using that combination twice per day for
only 4 days was dramatically superior to using topical 5-FU alone (combined with petrolatum
placebo).1 In the case of this study, the calcipotriene served to induce a molecule called
"thymic stromal lymphopoietin" (TSLP), an epithelium-derived cytokine that serves as a potent
inducer of antitumor immunity. Effectively, when used together, calcipotriene and 5-FU act
synergistically to induce tumor apoptosis and generate an immune/inflammatory response to
destroy the tumor cells.
The study would take the next logical step and expand/explore this combination of topical
therapies to SCCIS and superficially invasive SCC (but not deeply invasive or high-risk
cutaneous SCC), and do so without putting the patient at any increased risk for tumor
recurrence. The study would be limited to tumors involving the trunk and upper extremities
(excluding the hand). Following treatment with the topical chemotherapeutic medication,
tumors would be completely excised according to standard of care, and specimens would be sent
to pathology to determine if there was residual tumor/margin clearance. The potential benefit
of this intervention would be the establishment of a non-invasive treatment that leads to
minimal to no scarring or complications (akin to topical 5-FU alone) but would require a much
shorter and more tolerable treatment duration (1-2 weeks) compared to available alternatives.