Mohs Micrographic Surgery: Chemotherapeutic Agents Used in Cutaneous Oncology

Function

Chemotherapy works by inducing toxic effects on cells. These medications can inhibit cell proliferation by blocking specific phases of the cell cycle or by disrupting cellular metabolism. These mechanisms are specifically designed to be more toxic to rapidly dividing tumor cells than to normal tissue. Although these agents can cause some degree of toxicity to normal cells, they primarily affect rapidly proliferating tissues such as bone marrow, the epithelium of the small intestine, testicular tubules, and the hair matrix. Please see StatPearls' companion resource, "Cancer Chemotherapy," for more information.

Chemotherapy drugs are classified based on their mechanisms of action and include antimetabolites, alkylating agents, vinca alkaloids, antibiotics, and others. Antimetabolites, such as 5-fluorouracil (5-FU) and cytosine arabinoside, inhibit the S phase of DNA synthesis by binding to normal metabolites and forming inactive, defective molecules. Alkylating agents, including cyclophosphamide and busulfan, also target the S phase by alkylating DNA, thereby disrupting replication. Vinca alkaloids, such as vincristine and vinblastine, inhibit spindle formation during the metaphase of mitosis. Certain antibiotics, such as bleomycin, exert cytostatic effects by interfering with DNA transcription, RNA translation, or protein synthesis, making them effective chemotherapeutic agents.

Issues of Concern

Basal Cell Carcinoma

BCCs are the most common form of skin cancer, accounting for approximately 80% of nonmelanoma skin cancers.[1] BCCs are typically less aggressive than other types of cutaneous cancer, which makes systemic chemotherapy less frequently necessary. Treatment modalities include excision, curettage and electrodesiccation, micrographic surgery, cryotherapy, radiation, and topical therapies such as 5-FU cream and imiquimod, as well as intralesional agents. Intralesional agents used in treatment include 5-FU, bleomycin, methotrexate (MTX), interferon (IFN), and interleukin (IL)-2. Immunotherapies and targeted therapies are more commonly employed for advanced BCCs; however, these treatments are beyond the scope of this resource. 

Topical 5-FU is an FDA-approved treatment for superficial BCCs. As an antimetabolite, 5-FU inhibits thymidylate synthase, preventing DNA synthesis and cell proliferation. Topical 5-FU is typically applied twice daily for 4 to 6 weeks, with an inflammatory response typically starting 1 to 2 weeks into treatment. In a randomized clinical trial, 80.1% of patients with superficial BCCs achieved histological clearance with 5-FU.[2]

Intralesional chemotherapy with bleomycin, MTX, and 5-FU can also treat BCCs.[3] Miller and colleagues conducted a study involving 122 patients with nodular or superficial BCCs, which demonstrated a 91% response rate with intralesional 5-FU.[1] Bleomycin is an antibiotic and cytotoxic drug that inhibits the cell cycle and cleaves DNA.[4] Although bleomycin is more commonly used to treat refractory warts, there are reports of BCCs being successfully treated with repeated low-dose intralesional bleomycin.[5] Additionally, numerous studies have documented the use of bleomycin-mediated electrochemotherapy (ECT), in which an electrical pulse following intralesional injection enhances drug penetration and therapeutic efficacy.[1]

Another treatment option for BCC involves the use of alkylating agents.[6] These agents induce cell death by adding alkyl groups to the guanine bases of DNA. Alkylating agents are classified into 2 main categories—classic agents (such as cyclophosphamide, ifosfamide, and thiotepa) and platinum-based agents (such as cisplatin and carboplatin). Limited reports suggest that combining carboplatin and paclitaxel for refractory metastatic BCCs results in a favorable response, although it is associated with significant neurotoxicity.[7]

Squamous Cell Carcinoma

SCC is the second most common type of skin cancer.[8] Most early-stage SCC cases are treated surgically; however, approximately 5% may progress to advanced-stage disease.[9] Patients with advanced-stage SCC are often poor candidates for surgery and/or radiation and may present with metastatic disease. Treating advanced SCC can be challenging, with traditional approaches involving a combination of surgery, radiation, and systemic therapy. Before the development of immunotherapeutic agents such as cemiplimab, pembrolizumab, and nivolumab, chemotherapy was more commonly used in the management of advanced-stage SCC.[10]

Topical chemotherapy is one chemotherapeutic approach used in the treatment of SCC. This is commonly applied to actinic keratosis (AK), a precursor to SCC, and to SCC in situ. Topical 5-FU is frequently used in patients with AKs or SCC in situ who are poor surgical candidates or prefer to avoid surgery. A retrospective chart review by Neale et al reported a 92.9% success rate for SCC in situ treated with topical 5-FU.[4] 

Tirbanibulin is a topical ointment that inhibits tubulin polymerization, thereby halting cell division. This drug is approved for the treatment of AKs. In 2 randomized, placebo-controlled clinical trials, tirbanibulin demonstrated statistically significant clearance rates of 44% and 54%, respectively.[12] Although no clinical trials have directly compared tirbanibulin with conventional treatments for AKs, single-cohort studies suggest that it may have lower clearance rates than more established therapies.

In addition to surgery and topical therapies, early-stage SCC can be treated with intralesional chemotherapy, including 5-FU, MTX, and bleomycin. The use of 5-FU for SCC dates back to 1962, when Klein et al first reported its application.[11] Since then, numerous studies have documented the use of 5-FU for both SCC and keratoacanthoma (KA), which is a variant of SCC. In an open-label trial involving patients with well-defined SCCs, a cure rate of 96% was achieved following 4 to 6 injections of 5-FU.[12] Some evidence also suggests that intralesional 5-FU may be superior to surgery for treating large KAs or those located in cosmetically sensitive areas. 

Although intralesional 5-FU is the most commonly used treatment, MTX and bleomycin are 2 other chemotherapies used intralesionally. MTX, a dihydrofolate reductase inhibitor, blocks thymidine synthesis. In a retrospective analysis by Annest et al, 38 KAs treated with intralesional MTX showed a cure rate of 92%.[13] Compared to 5-FU, MTX requires fewer treatments with longer intervals between injections, is a more affordable treatment option, and causes less pain.[1] A few reports have documented the use of intralesional bleomycin in treating KAs. In a case report, a KA centrifugum marginatum was injected weekly with 0.2 mg of bleomycin for 3 sessions, with no recurrence observed after 4 years of follow-up.[14] In another case, a 1:1 mixture of bleomycin and bupivacaine was injected into a KA, resulting in lesion flattening after three treatments and no recurrence after 18 months of follow-up.[15]

Chemotherapy may also be used for patients with advanced-stage SCC who are ineligible for or refractory to checkpoint inhibitor immunotherapy. A combination of carboplatin and paclitaxel has been considered a viable option in these cases. Cisplatin, either as monotherapy or in combination with agents such as 5-FU, doxorubicin, bleomycin, or adriamycin, has also been used to treat advanced cutaneous SCC, although supporting data are limited.[16] 

A preoperative regimen of cisplatin and bleomycin achieved an 80% response rate, while the combination of cisplatin, 5-FU, and bleomycin demonstrated an 84.6% response rate.[17] However, these combinations of chemotherapeutics are often avoided due to significant toxicities, particularly in the geriatric population, which constitutes a substantial portion of the SCC population. A regimen combining IFN-α, retinoic acid, and cisplatin was used for unresectable SCCs, resulting in a 34% response rate.[18] Cartei et al reported a 64% improvement rate in patients treated with oral 5-FU.[19]

Melanoma

The FDA approval of immunotherapy agents such as ipilimumab and vemurafenib marked a significant advancement in the management of metastatic melanoma, representing a transition away from cytotoxic treatments. These 2 agents are the first to demonstrate an overall survival benefit in the treatment of melanoma. In addition to ipilimumab and vemurafenib, IL-2, IFN-α, and dacarbazine are the only FDA-approved drugs for melanoma.[20] Although many chemotherapeutics have been studied for melanoma treatment, only dacarbazine has received FDA approval.

Unlike BCC and SCC, intralesional chemotherapy is generally not used for the treatment of melanoma, as the Breslow depth is the most significant prognostic factor. However, a few studies have explored the use of intralesional chemotherapies in a palliative setting for melanoma. One such approach, intralesional bleomycin-mediated ECT, has been reported for palliative treatment of metastatic melanoma, where it was used to alleviate or manage metastatic disease in skin and soft tissue. However, it did not prevent the formation of new metastatic lesions.[21] A complete response was observed in 89.3% of melanomas treated with intralesional bleomycin and ECT, while 9.5% showed a partial response. Intralesional bleomycin combined with ECT was more effective than bleomycin alone in the palliative treatment of melanoma.[1]

Dacarbazine, an alkylating agent, is an FDA-approved chemotherapeutic for melanoma.[20] This medication has a modest response rate of 10% to 20% and a progression-free survival of 3 to 6 months. Temozolomide (TMZ), a prodrug and analog of dacarbazine, was evaluated in a phase III trial and did not demonstrate significantly greater efficacy.[20] TMZ demonstrated an overall survival of 7.7 months, compared to 6.4 months with dacarbazine. Progression-free survival was 1.9 months with TMZ and 1.5 months with dacarbazine. Both agents cross the blood-brain barrier, making them suitable options for treating metastatic melanoma with brain involvement. Although various dosing regimens have been published, no single regimen has shown superior efficacy. TMZ is an oral medication, offering easier dosing compared to the intravenous formulation of dacarbazine. Adverse effects include leukopenia, anemia, nausea, and vomiting. Bone marrow suppression is more significant with TMZ than with dacarbazine, and there is a more significant risk for opportunistic infections.

Melphalan, which disrupts DNA synthesis and transcription by binding to guanine and inducing cross-linking, has demonstrated significant improvements in both hepatic and overall progression-free survival when used as a first-line agent compared to liver-directed therapies or immunotherapy. Similar benefits have also been observed when used as a second-line treatment.[22]

Nitrosoureas, including fotemustine, carmustine, and lomustine, have demonstrated similar response rates of 10% to 18%, comparable to those of temozolomide or dacarbazine.[20] Although these agents are approved in Europe, they have not received FDA approval in the United States. Nitrosoureas have a less favorable adverse effect profile than other chemotherapeutic agents used in melanoma, with more pronounced bone marrow suppression and a higher incidence of alopecia. In patients without brain metastases, fotemustine has been shown to significantly prolong the time to the development of brain metastases compared to dacarbazine.[20]

Multiple other chemotherapeutic agents have been studied for melanoma, although they demonstrate low response rates. Vinca alkaloids, including vindesine, vinblastine, vincristine, and vinorelbine, have a response rate of 10% to 20% with a progression-free survival of 2 to 4 months, comparable to dacarbazine or TMZ.[20] These medications inhibit tubulin polymerization, arresting cells in metaphase and causing cell apoptosis. Common adverse effects include neuropathy, gastrointestinal symptoms, and bone marrow suppression. The mechanism of action of taxanes works by stabilizing microtubules and interfering with their disassembly. This mechanism contrasts with vinca alkaloids, which destabilize microtubules.

In a randomized phase III trial, paclitaxel and TMZ showed no significant difference in overall survival outcomes.[20] Platinum agents such as cisplatin and carboplatin have been studied less extensively, but most available data suggest a response rate of 15% to 20%. More recent investigations have focused on a nanoparticle formulation of paclitaxel, known as nab-paclitaxel. A study reported a response rate of 22% in chemotherapy-naive patients and 3% in those who had previously received chemotherapy.

Although immunotherapy alone provides a significant survival benefit, some studies have explored chemoimmunotherapy regimens, which are not commonly used. IFN-α and IL-2 are the 2 most commonly combined immunological agents with chemotherapy in published studies. These combinations have shown response rates ranging from 27% to 64%.[20] However, IL-2 introduces significant dose-dependent toxicities, and its efficacy is also dose-dependent, which limits its utility. As a result, IL-2 is not widely used outside of clinical trial settings.

The response rate with single-agent chemotherapy is modest, leading to the use of combination therapies. The Dartmouth regimen, which includes cisplatin, dacarbazine, carmustine, and tamoxifen, achieved a response rate of 55%. However, it was not statistically more effective than dacarbazine monotherapy in clinical trials.[24] Another regimen, combining cisplatin, vinblastine, and dacarbazine, had a response rate of 40%. Given the overall limited efficacy of chemotherapy for melanoma, it is not routinely used.

Merkel Cell Carcinoma

MCC is an aggressive and rare neuroendocrine skin cancer with a high metastatic potential. Notably, it is estimated that approximately 50% of patients die due to metastasis or recurrence, with the highest rate of recurrence occurring within the first 2 years following treatment.[23] Single-agent immunotherapy, such as avelumab or pembrolizumab, is preferred over chemotherapy for its better tolerability and efficacy.

For patients who are not candidates for immunotherapy, chemotherapy can be considered. Chemotherapeutics have a response rate of 53% to 76%, but their impact on overall survival is uncertain, as the response is often not durable, and there are significant risks of toxicity.[24] No randomized trials have been conducted on chemotherapy for metastatic MCC.

The preferred chemotherapeutic options for MCC include carboplatin plus etoposide, cisplatin plus etoposide, and cyclophosphamide/doxorubicin/vincristine. Among these, carboplatin plus etoposide is the regimen of choice, with an estimated response rate of 60%.[25]

Clinical Significance

Surgical intervention is the gold standard for managing skin cancers. However, systemic therapies are an option for patients who are unable or unwilling to undergo surgery or have advanced disease. With the development of immunotherapy and targeted agents, the use of systemic chemotherapeutics in treating skin cancers has decreased. Nevertheless, for patients who are ineligible for or cannot tolerate immunotherapy or targeted therapies, chemotherapy remains a viable alternative.

Despite the limited use of systemic chemotherapy, topical and intralesional chemotherapy are more commonly utilized, as mentioned earlier. Physicians should thoroughly discuss the expected course of treatment with patients, including potential adverse effects, the need for laboratory monitoring, and the required clinical follow-up.

Other Issues

Many studies evaluating chemotherapy for skin cancers have limitations, such as the absence of prospective randomized trials, the use of various treatment regimens, small sample sizes, heterogeneous patient populations, and a lack of long-term follow-up. Few, if any, randomized controlled trials provide guidance on treatment regimens, and no formal treatment guidelines exist for systemic chemotherapy.

Enhancing Healthcare Team Outcomes

As dermatology continues to grow, incorporating a diverse range of clinical care providers, it is essential for all healthcare team members to stay informed about the latest therapeutic options. The clinical effectiveness of chemotherapeutic regimens and their adverse effect profiles can often be optimized with proper access to care, which involves more than just clinicians in clinical settings.

Chemotherapy treatment decisions should be made within a multidisciplinary framework that includes surgical oncologists, medical oncologists, radiation oncologists, and pharmacists. This collaborative approach promotes comprehensive care, facilitates the effective management of toxicities, enhances patient outcomes, and encourages the exchange of expertise. Ethical principles should guide all treatment decisions, with an emphasis on respecting patient autonomy and ensuring informed consent.