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Treatment of Cutaneous Malignancies With Topical, Oral, and Injectable Medication
Introduction
Skin cancer is one of the most prevalent forms of cancer worldwide, and its incidence continues to rise. According to the Skin Cancer Foundation, 1 in 5 Americans will be diagnosed with skin cancer by the age of 70. This category includes various types, such as basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and melanoma, each presenting unique challenges in management and treatment. Current treatment options range from surgical excision and Mohs surgery to radiation therapy and systemic therapies, including chemotherapy and biologics. These treatment approaches aim to eradicate tumors while minimizing cosmetic and functional impairments. Topical and oral chemotherapeutic agents, as well as biologics, are increasingly utilized in managing skin cancer. Consequently, clinicians must be well-informed about the efficacy, potential adverse effects, and clinical considerations of these medications.
Clinical Significance
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Clinical Significance
5-Fluorouracil
5-Fluorouracil (5-FU) is a thymidylate synthase inhibitor that induces apoptosis in rapidly dividing cells.[1] As monotherapy, topical 5% 5-FU, applied twice daily for 2 to 4 weeks, is effective for treating actinic keratoses and preventing cutaneous SCC (cSCC). A randomized trial demonstrated that this regimen could reduce the risk of SCC requiring surgery by 75% on the face and ears at a 1-year follow-up; however, this benefit diminishes after 2 years. Additionally, topical 5% 5-FU cream is approved by the US Food and Drug Administration (FDA) for the treatment of superficial BCC. However, long-term studies suggest that topical imiquimod provides a higher clearance rate at 3 years than topical 5-FU for treating superficial BCC.[2]
Calcipotriene, a synthetic vitamin D3 analog, has been studied for the chemoprevention of cSCC due to its ability to modulate cellular differentiation and inhibit keratinocyte proliferation by binding to the vitamin D receptor. The mechanism of action of calcipotriene includes promoting apoptosis in UV-damaged keratinocytes, making it a potential option for cancer prevention.[3]
When combined with 0.005% calcipotriol (also known as calcipotriene in the United States), topical 5% 5-FU can be applied twice daily in a 4-day treatment regimen. A double-blind, randomized controlled trial demonstrated the efficacy of this combination in treating actinic keratoses.[3] Additionally, the combination treatment has been shown to prevent SCC for up to 3 years, likely due to the robust induction of CD4+ T-cell–mediated immunity and the sustained presence of these cells in the epidermis.[3][4] Furthermore, a small pilot study indicates that the combination of 5% 5-FU and 0.005% calcipotriene cream shows promise for treating SCC in situ. However, topical 5-FU, either as monotherapy or combined with calcipotriol, does not prevent BCC.[5][4]
Intralesional 5-FU is also utilized to treat SCC in cases where surgical intervention is not preferred or feasible. In a retrospective study, intralesional 5-FU achieved effective treatment in 92% of SCCs measuring less than 2 cm in diameter, with only one reported recurrence of keratoacanthoma. Reported adverse effects include discoloration, hyperpigmentation, local erythema, scaling, tenderness, localized pruritus (with or without erythema), and injection site infections.[6] Additionally, intralesional 5-FU demonstrated a 91% histologic clearance rate for both superficial and nodular BCC.[7] Although limited data are available, intralesional 5-FU is an effective, minimally invasive treatment for low-risk SCC and BCC.
Common adverse effects of 5-FU include pain, pruritus, erythema, and crusting, while infection and ulceration occur less frequently.[8] These adverse effects may be mitigated by reducing the treatment frequency (eg, daily versus weekly) or using a lower concentration of 5-FU (eg, 5% versus 0.5%) while extending the treatment duration to 4 to 6 weeks. However, given its dose-dependent nature, these alternative regimens have not been well studied and may reduce the efficacy of 5-FU therapy.
Several studies have explored various topical 5-FU formulations aimed at minimizing adverse effects, such as incorporating a skin barrier emulsion, petrolatum, drug-delivering liposomes, or glycolic acid, with some promising results. However, further research is needed to confirm their effectiveness.[9] A rare but serious complication, including severe lethargy, fever, mucositis, weight loss, and neutropenia, may occur in patients with dihydropyrimidine dehydrogenase deficiency, as this enzyme is crucial in the rate-limiting step of 5-FU metabolism.[10]
Imiquimod
Imiquimod stimulates the production of interferon-alpha (IFN-α), tumor necrosis factor-alpha (TNF-α), interleukins (ILs)-6 and 8, and activates CD4+ and CD8+ T cells as well as mast cells. Imiquimod is typically dosed at a 5% concentration and applied 3 times weekly for 12 to 16 weeks for the treatment of actinic keratoses.[9] Higher dosages exceeding 3 applications per week are associated with systemic adverse effects and decreased tolerance.[11] Studies have demonstrated that imiquimod at a 3.75% concentration is effective in treating actinic keratoses after 8 weeks of treatment.[12]
The FDA has approved topical imiquimod 5% cream for the treatment of superficial BCC in cases where surgery is not preferred. Studies have reported a 100% clearance rate at 6-week follow-up and sustained clearance rates of 77.9% to 80.4% at 5-year follow-up when applied twice daily for 12 weeks.[13][14][15] However, additional long-term studies are needed to further evaluate the sustained effectiveness of imiquimod in treating superficial BCC.
Common adverse effects include local erythema, pain, erosion, inflammation, scabbing, and pigmentation. These cutaneous reactions also reflect imiquimod's effectiveness in activating the dermal immune response to target rapidly dividing cells.[16][17] Approximately 7 to 11 days after the onset of cutaneous reactions, some patients may experience systemic flu-like symptoms, including myalgia, fever, fatigue, and headache. In organ transplant patients, the potential risk of imiquimod triggering autoimmune-induced organ rejection should be carefully considered.[9]
Retinoids
Retinoids, vitamin A derivatives, have been explored for the chemoprevention of cSCC, particularly in high-risk populations. They exert their effects by modulating retinoic acid receptors and retinoid X receptors, which leads to reduced keratinocyte proliferation and enhanced cellular differentiation, potentially preventing malignant transformation.[18]
Acitretin has demonstrated efficacy in preventing cSCC in immunocompromised patients. In a randomized study of organ transplant recipients, acitretin significantly reduced the incidence of new cSCCs compared to a placebo.[18] Similar benefits were observed with supplementation of 25,000 IU of oral retinol. After 5 years, moderate-risk patients receiving oral retinol exhibited a reduced incidence of new cSCCs compared to the placebo group; however, the risk of developing new BCCs remained unchanged.[19] Despite these advantages in the chemoprevention of cSCCs, discontinuation of oral retinoids has been associated with a rebound effect, resulting in an increased incidence of cSCCs following cessation of therapy.[20][21]
Retinoid therapy is associated with significant adverse effects, particularly with long-term use. Common toxicities include xerosis, cheilitis, mucosal dryness, and hyperlipidemia. More serious complications, such as hepatotoxicity, skeletal abnormalities, and teratogenicity, require careful monitoring and strict pregnancy prevention measures during treatment.[22] Although retinoids show promise in reducing cSCC incidence in high-risk populations, their adverse effect profile often limits their long-term use.
Topical Photosensitizers and Photodynamic Therapy
Topical aminolevulinic acid (ALA) and methyl aminolevulinate (MAL) are photosensitizing agents used in photodynamic therapy (PDT) for the treatment of actinic keratoses and superficial nonmelanoma skin cancers, particularly targeting superficial and in situ lesions. ALA is a hydrophilic, naturally occurring precursor in the heme biosynthesis pathway, whereas MAL is a methyl ester of ALA designed to be more lipophilic, enhancing its cutaneous absorption. Both agents work by promoting the production of protoporphyrin IX (PpIX)—a photosensitizer that accumulates in dysplastic cells. When exposed to specific wavelengths of light, PpIX generates reactive oxygen species, leading to the selective apoptosis and necrosis of tumor cells. Due to its hydrophilic properties, ALA penetrates less deeply than MAL. ALA-PDT uses blue light at 417 nm for activation, whereas MAL-PDT uses red light at 630 nm. As a result, MAL-PDT is more effective for treating deeper lesions, such as superficial nonmelanoma skin cancers, while ALA-PDT is more effective for treating superficial actinic keratoses.[23]
PDT is recommended as a first-line treatment for patients with multiple actinic keratoses, offering enhanced cosmetic outcomes and good patient tolerability.[23] Clearance rates for actinic keratoses with PDT range from 50% to 71% after a single session, increasing to 88% to 90% with 2 or more treatments.[24] For superficial BCC and Bowen disease, PDT is considered an alternative to surgical excision, particularly when surgery is contraindicated or when preserving cosmetic appearance is a priority.[23]
In the case of superficial BCCs, MAL-PDT demonstrated clearance rates of 85% to 97% at 3 months posttreatment, with long-term follow-up showing sustained clearance in 75% to 95% of cases at 60 months. In contrast, the clearance rate for nodular BCC is lower, ranging from 75% to 82% at 3 months and approximately 77% at 60 months. Despite these favorable outcomes, the efficacy of PDT is limited in invasive or deeply infiltrative cSCC due to the superficial penetration of both photosensitizers and light energy. As a result, recurrence rates in such cases may be higher compared with surgical excision.[25]
Common adverse effects of PDT include localized skin reactions such as erythema, edema, and pain during light exposure, which typically resolve within a few days.[23][26] Some patients may also develop blistering, crusting, or hyperpigmentation at the treatment site.[26] Photosensitivity reactions are a significant concern, particularly within the first 48 hours after the procedure, due to residual PpIX remaining in the skin during this period.[26] Therefore, adequate sun protection is essential for up to 2 days following PDT to prevent the risk of photosensitivity reactions.
Sonic Hedgehog Inhibitors
BCC is the most common skin cancer in the United States and is characterized by a high cure rate and low mortality risk. The Sonic Hedgehog (Shh) pathway is mutated in approximately 90% of sporadic BCC cases. Shh pathway inhibitors, such as vismodegib and sonidegib, target the transmembrane protein Smoothened (Sm), thereby suppressing the Shh signaling pathway and inhibiting cellular proliferation in BCC.[27]
In 2012, vismodegib, an oral systemic medication, was first approved to treat locally advanced and metastatic BCCs. Two large clinical trials have demonstrated that vismodegib yields a response rate of 30% to 60% in these conditions. In these trials, patients received 150 mg of vismodegib daily for an average duration of 9.8 months and 7.6 months, respectively. Among patients with metastatic BCC, 30% to 50% showed a partial response (PR) to vismodegib. For patients with locally advanced BCC, 13% to 21% achieved a complete response (CR), as indicated by the absence of BCC in biopsy specimens, while 22% to 47% experienced a partial response.[28][29]
Sonidegib later received FDA approval as a first-line treatment for locally advanced BCC at a daily dose of 200 mg. Compared to vismodegib, sonidegib demonstrated an earlier and higher overall response rate (ORR) of 60.6%, with a complete response rate of 21.2% and a partial response rate of 39.4% at 18 months of follow-up. In contrast, vismodegib showed an ORR of 47.6%, with a complete response of 22.2% and a partial response of 25.4% at 21 months of follow-up.[30] Sonidegib was also associated with a lower rate of progressive disease (1.5%) compared to vismodegib (12.7%), consistent with the development of treatment resistance observed with vismodegib.[30][31] Additionally, sonidegib demonstrated a longer median duration of response and median progression-free survival (PFS) of 30 months, compared to 21 months with vismodegib.[29][32]
Commonly reported adverse effects of Shh inhibitors include muscle spasms, alopecia, and dysgeusia.[33] Studies have shown that treatment cessation occurs in approximately 5% of patients with operable BCC and 36% of patients with locally advanced or metastatic BCC.[34][35] Muscle spasms, which affect 49% to 76% of patients, most commonly occur in the lower extremities at night and tend to be more prevalent in older individuals.[36] Dysgeusia, affecting 50% to 71% of patients, results from the impact of Shh inhibitors on the number of Shh-expressing type IV taste cells.[37][38] Reversible alopecia affects 46% to 66% of patients because Shh inhibitors prevent hair follicles from transitioning from the telogen to the anagen phase.[37] However, it has been reported that most cases of alopecia improve within 24 weeks after treatment cessation.[34] Early discussion of the expected adverse effects of Shh inhibitors and strategies to mitigate them is crucial for ensuring treatment adherence.[33]
Interleukin-2
IL-2 therapy was historically a cornerstone of immunotherapy for advanced skin cancers, particularly metastatic melanoma, before the emergence of immune checkpoint inhibitors. IL-2 is a cytokine that promotes T-cell activation and proliferation, enhancing immune-mediated tumor destruction by expanding cytotoxic T lymphocytes and natural killer cells.[39] Systemic high-dose IL-2 therapy has demonstrated durable complete responses in a subset of patients with metastatic melanoma. In pivotal trials, high-dose IL-2 achieved an ORR of 16%, with 6% of patients attaining complete responses and 10% achieving partial responses.[40]
Intralesional IL-2 injections have emerged as an alternative treatment for localized skin cancers, particularly in-transit melanoma metastases. Small studies have reported complete response rates of up to 69% in localized melanoma lesions, with a more favorable safety profile compared to systemic IL-2 therapy. A study reported a 2-year survival rate of 77% for patients with stage IIIB/IIIC disease and 53% for those with stage IV disease following intralesional IL-2 treatment.[41] The National Comprehensive Cancer Network (NCCN) recommends intralesional IL-2 as a second-line treatment option for unresectable stage III in-transit melanoma when intralesional talimogene laherparepvec (T-VEC) is unavailable or contraindicated.[42]
The primary limitation of IL-2 therapy is its toxicity profile. Systemic administration is commonly associated with significant adverse effects, including flu-like symptoms, hypotension, capillary leak syndrome, neurotoxicity, and multiple-organ dysfunction, necessitating administration in specialized centers capable of providing intensive supportive care.[40] Although intralesional administration offers a safer alternative, it can still cause localized inflammation and pain at the injection site.[41] With the introduction of immune checkpoint inhibitors and targeted therapies—both offering higher response rates and improved survival—the role of IL-2 in metastatic melanoma has declined. Nonetheless, IL-2 remains a treatment option for select patients, particularly when other therapies are contraindicated or unavailable.
Interferon-alpha
Due to its immunomodulatory and antitumor properties, IFN-α has been used in the treatment of skin cancers, particularly high-risk melanoma. IFN-α functions by stimulating antigen presentation, enhancing the activity of cytotoxic T cells, and inhibiting tumor cell proliferation.[43][44]
The efficacy of IFN-α in melanoma was demonstrated in the pivotal Eastern Cooperative Oncology Group (ECOG) 1684 trial, where high-dose IFN-α significantly improved relapse-free survival (RFS) and, to a lesser extent, overall survival compared to observation in patients with high-risk, resected melanoma. The median RFS increased from 1 to 1.7 years, and the median overall survival increased from 2.7 to 3.8 years.[43][44] Subsequent trials, such as the European Organization for Research and Treatment of Cancer (EORTC) 18991 study, demonstrated that the 4-year RFS was 45.6% in the IFN-α group versus 38.9% in the observation group, although the impact on overall survival remained limited.[45]
IFN-α therapy is associated with significant adverse effects that often limit its clinical utility. Common toxicities include flu-like symptoms (eg, fever, fatigue, and chills), myelosuppression, hepatotoxicity, and neuropsychiatric symptoms such as depression and cognitive disturbances.[46] These adverse effects may necessitate dose reductions or early discontinuation in a significant proportion of patients.
Although IFN-α has shown efficacy in preventing recurrence in high-risk melanoma, its use has largely been supplanted by immune checkpoint inhibitors due to their superior efficacy and improved tolerability. Agents such as nivolumab and pembrolizumab, which target the programmed cell death-1 (PD-1) pathway, have shown significant improvements in relapse-free and overall survival in the adjuvant setting, establishing them as the standard of care for high-risk melanoma.[47][48]
Immunotherapy—PD-(L)1 Inhibitors and CTLA-4 Inhibitors
PD-1 and its ligand (PD-L1), as well as cytotoxic T-lymphocyte–associated protein-4 (CTLA-4), are immunomodulators that downregulate the body's immune response by suppressing T-cell activation. Inhibitors targeting these immunomodulatory pathways can reverse this suppression, thereby enhancing T-cell activity and enabling the immune system to target tumor cells better.
Melanoma
Ipilimumab, a CTLA-4 inhibitor, was first approved by the FDA in 2011 for the treatment of metastatic melanoma.[49] Initial studies demonstrated improved median survival rates compared to previous treatments, such as IL-2 or the glycoprotein 100 vaccine.[50] A long-term follow-up study showed a 5-year overall survival rate of 18% with ipilimumab plus dacarbazine, compared to 9% for those receiving placebo plus dacarbazine in treatment-naive advanced melanoma patients.[51]
Randomized trials have demonstrated that PD-1 inhibitors, such as nivolumab and pembrolizumab, achieve higher response rates than traditional treatments, including dacarbazine and ipilimumab, in advanced melanoma. For instance, the KEYNOTE-006 trial reported that pembrolizumab significantly improved overall survival and PFS compared to ipilimumab.[52] Long-term follow-up studies have reinforced these findings, indicating that both pembrolizumab and nivolumab, when used as monotherapies, offer superior long-term PFS and overall survival compared to ipilimumab. For example, the CheckMate 067 trial demonstrated sustained survival benefits, with a median PFS of 6.9 months for nivolumab monotherapy and 11.5 months for the combination of nivolumab and ipilimumab, compared to just 2.9 months for ipilimumab monotherapy in patients with advanced melanoma.[53]
Combining CTLA-4 and PD-1 inhibitors, such as ipilimumab and nivolumab, has demonstrated superior treatment efficacy compared to monotherapy with either agent alone. Randomized trials have demonstrated that combination therapy significantly improves response rates and extends median PFS compared to monotherapy.[54][55] The CheckMate 067 trial supported this approach, reporting 4-year overall survival rates of 53% for the nivolumab plus ipilimumab combination, 46% for nivolumab monotherapy, and 30% for ipilimumab monotherapy.[53] Similarly, the CheckMate 069 trial reported a 3-year overall survival rate of 68% for the nivolumab plus ipilimumab group compared to 54% for ipilimumab monotherapy in patients with advanced melanoma.[54]
PD-L1 inhibitors, such as atezolizumab, durvalumab, and avelumab, are immune checkpoint inhibitors that block the PD-L1 protein, thereby preventing its interaction with the PD-1 receptor on T cells. In melanoma, PD-L1 inhibitors have demonstrated moderate efficacy compared to PD-1 inhibitors, such as nivolumab and pembrolizumab. Atezolizumab, however, has demonstrated enhanced response rates when used in combination with targeted therapies such as cobimetinib and vemurafenib in patients with BRAF-mutant melanoma. The IMspire150 trial showed that the combination of atezolizumab, vemurafenib, and cobimetinib achieved a median PFS of 15.1 months, compared to 10.6 months in the control group that received a placebo, vemurafenib, and cobimetinib for the treatment of BRAF-positive advanced melanoma.[56] However, as monotherapy, PD-L1 inhibitors have shown limited clinical benefits in melanoma, emphasizing the need for combination strategies.
Nonmelanoma skin cancers
Cemiplimab, a PD-1 inhibitor, has gained FDA approval for treating metastatic or locally advanced SCC and advanced BCC following prior treatment with a hedgehog pathway inhibitor, or for patients who are not candidates for such inhibitors. In a pivotal phase 2 trial, cemiplimab demonstrated significant efficacy in patients with locally advanced BCC, achieving an ORR of 31% in those who had progressed on or were intolerant to hedgehog pathway inhibitors.[57] The NCCN recommends cemiplimab as a treatment option for advanced BCC when surgical intervention is contraindicated or not feasible.[58]
For cSCC, cemiplimab has demonstrated robust efficacy, with ORRs ranging from 44% to 50% in patients with locally advanced or metastatic disease.[59][60] Pembrolizumab, another PD-1 inhibitor, has also demonstrated efficacy in cSCC, achieving an ORR of 34% in patients with locally advanced, recurrent, or metastatic disease.[61] Additionally, a retrospective study further indicated that immunotherapy offers superior survival outcomes compared to other systemic therapies for the treatment of advanced cSCC.[62]
Avelumab has also shown significant efficacy in treating Merkel cell carcinoma (MCC). In the JAVELIN Merkel 200 trial, avelumab achieved an ORR of 33%, with complete responses observed in 11.4% of patients. Durable responses were observed in both chemotherapy-refractory and treatment-naive patients with metastatic MCC. The median duration of response was 40.5 months, and the median overall survival was 12.6 months.[63][64][65] These findings supported the FDA approval of avelumab as the first PD-L1 inhibitor for metastatic MCC.
Retifanlimab, a humanized anti-PD-1 monoclonal antibody, has shown promise in the treatment of MCC. In the phase 2 POD1UM-201 trial, retifanlimab achieved an overall response rate (ORR) of 46.2%, with complete responses in 12.3% of patients and partial responses in 33.8% of patients. At the time of reporting by Grignani et al at the 2023 European Society for Medical Oncology Congress in Spain, the median overall survival had not yet been reached.
Immune-related adverse events
Immune-related adverse events (irAEs) are complications induced by immunotherapy resulting from an enhanced T-cell antitumor response, which is triggered following the inhibition of immune checkpoints. Notably, a higher incidence and severity of irAEs have been associated with improved treatment response rates.[55] IrAEs occur in approximately 74% of patients receiving anti–PD-1 or anti–PD-L1 inhibitors, 89% with anti–CTLA-4 inhibitors, and up to 90% with combination therapy.[66] Due to the nonspecific activation of T-cell responses, irAEs can affect multiple organ systems. Commonly reported irAEs include diarrhea, colitis, dermatitis, pruritus, vitiligo, myalgia, and pneumonitis.[67] However, a comprehensive discussion of irAE management is beyond the scope of this activity.
PD-1 inhibitors generally exhibit a more favorable adverse effect profile than ipilimumab during the initial treatment period. A systematic review and meta-analysis reported that the incidence of irAEs is comparatively lower with PD-1 inhibitors than CTLA-4 inhibitors (eg, ipilimumab). In contrast, combination therapies of PD-1 inhibitors and CTLA-4 inhibitors are associated with higher incidences of irAEs compared to monotherapies.[68] Both the CheckMate 067 and CheckMate 069 trials reported higher rates of treatment-related adverse events with combination therapy. In CheckMate 067, combination therapy was associated with increased rates of grade 3–4 treatment-related adverse events, including immune-related events such as colitis, hepatitis, and endocrinopathies, resulting in a higher rate of early treatment discontinuation in the combination arm.[53] However, while early-onset adverse events are less frequent with PD-1 inhibitors, new irAEs can emerge beyond 12 weeks of treatment. In contrast, ipilimumab-associated adverse events often taper off after this period.[53][69] This distinction highlights the importance of ongoing monitoring of patients receiving PD-1 inhibitors, even after the initial treatment phase.
Targeted Therapy With BRAF and MEK Inhibitors
Genomic sequencing from the Cancer Genome Atlas Network has identified 3 common mutations in melanoma—BRAF (35%-50%), RAS (10%-25%), NF1 (14%), and triple-wild type mutations involving c-KIT and GNAQ (10%).[70] Targeted therapy with BRAF inhibitors has paved the way for investigating other particular kinase-targeting agents across various cancers.[70] When used as monotherapy, BRAF inhibitors produce a treatment response rate of approximately 50%, with rapid onset of action within 2 weeks. However, melanoma treated with BRAF inhibitors often relapses, with a median PFS of 6 to 8 months, due to acquired resistance from paradoxical activation of the mitogen-activated protein kinase (MAPK) pathway.[71] Combining BRAF and MEK inhibitors, which target the downstream components of the MAPK pathway, helps to counteract this resistance. Studies have demonstrated that the combination of BRAF and MEK inhibitors improves overall survival, response rates, and median PFS compared to monotherapy with BRAF inhibitors.[72][73][74] The FDA has approved the combination therapies vemurafenib/cobimetinib, dabrafenib/trametinib, and encorafenib/binimetinib for treating BRAFV600 mutant melanoma.[49]
Commonly reported adverse events with monotherapy of BRAF inhibitors include nausea, fatigue, exanthematous rash, arthralgia, cSCC, keratoacanthoma, pruritus, and palmar-plantar dysesthesia.[75] Frequently reported adverse events with monotherapy of MEK inhibitors include diarrhea, papulopustular and morbilliform rash, ocular toxicity, nausea, and vomiting.[76] When BRAF inhibitors are combined with MEK inhibitors, the risk of secondary SCC and keratoacanthoma decreases compared to BRAF monotherapy, as paradoxical activation of the MAPK pathway is inhibited.[77] However, gastrointestinal adverse effects, such as diarrhea, nausea, and vomiting, increase, as well as cardiac and ocular adverse effects.[76]
Capecitabine
Capecitabine, an oral prodrug of 5-FU, has been explored as a systemic treatment for advanced and recurrent cSCC, particularly in patients who are not candidates for surgical excision or radiation therapy. Capecitabine is enzymatically converted into 5-FU, which inhibits thymidylate synthase, disrupts DNA synthesis, and leads to tumor cell apoptosis.[78]
Capecitabine has demonstrated efficacy in both the treatment and chemoprevention of cSCC, especially in high-risk populations. Capecitabine can also be used as an adjunct therapy in locally advanced cSCC, resulting in partial responses and prolonged disease control in patients unfit for surgery or radiation therapy. However, data from randomized controlled trials remain limited, and their use for cSCC remains off-label.[78]
The adverse effect profile of capecitabine can be significant, often limiting its long-term use. One of the most common adverse effects is hand-foot syndrome, characterized by erythema, swelling, and desquamation of the palms and soles. Other frequently observed toxicities include gastrointestinal symptoms such as diarrhea, nausea, vomiting, and mucositis. Myelosuppression and hepatotoxicity have also been reported, although they are less common.[78] Regular monitoring and dosage adjustments can help manage these toxicities, but severe cases may necessitate treatment discontinuation.
Talimogene Laherparepvec
T-VEC is a genetically modified oncolytic herpes simplex virus type 1 engineered to selectively replicate within tumor cells while expressing granulocyte-macrophage colony-stimulating factor (GM-CSF). GM-CSF enhances the recruitment and activation of antigen-presenting cells, thereby amplifying the antitumor immune response.[79]
The efficacy of T-VEC in the treatment of advanced melanoma was demonstrated in the phase 3 OPTiM trial. This study compared intralesional T-VEC injections to GM-CSF alone and reported a significantly higher durable response rate with T-VEC (16.3%) compared to GM-CSF (2.1%) in patients with unresectable stage IIIB-IV melanoma.[80] The same study noted that the durable response rate increased to 33% with T-VEC for the treatment of stage IIIB or IIIC melanoma, compared to 0% with GM-CSF, while the durable response rate is more modest in more advanced stages of melanoma. Long-term analysis further confirmed improved ORRs and complete response rates, particularly in patients with earlier-stage unresectable melanoma.[81] As a result, T-VEC has been FDA-approved for the treatment of unresectable cutaneous, subcutaneous, and nodal lesions in melanoma. Currently, the NCCN recommends intralesional T-VEC treatment for patients with unresectable stage II in-transit melanoma.[42]
The impact of T-VEC on overall survival remains modest when used as a monotherapy, with a median overall survival of 23.3 months in the OPTiM trial, compared to 18.9 months for GM-CSF.[80] However, combination strategies with immune checkpoint inhibitors, such as pembrolizumab, have shown promise, demonstrating an ORR of 62% and a complete response rate of 33%. These findings suggest a synergistic effect that enhances systemic antitumor immunity.[82]
Common adverse events associated with T-VEC include flu-like symptoms, such as fever, chills, fatigue, and injection site reactions. Serious adverse events are rare but can consist of cellulitis and irAEs, which may occur likely due to the virus's immune-stimulating properties.[80] T-VEC represents an effective localized therapy for advanced melanoma, particularly in patients with injectable lesions and low tumor burden. Ongoing trials continue to explore its potential in combination therapies to further improve survival outcomes.
Tebentafusp
Tebentafusp, a bispecific T-cell receptor therapy, represents a significant advancement in the treatment of metastatic uveal melanoma, which is a rare and aggressive ocular malignancy with limited effective systemic treatment options. This agent is engineered to target glycoprotein 100 (gp100), which is a melanocyte-specific antigen expressed on uveal melanoma cells, thereby redirecting cytotoxic T cells to recognize and eliminate these cancer cells.[83]
In the pivotal phase 3 IMCgp100-202 trial, tebentafusp demonstrated a substantial improvement in overall survival compared to standard therapies. Among HLA-A*02:01-positive patients with metastatic uveal melanoma, the 1-year overall survival rate was 73% with tebentafusp compared to 59% in the control group, which received investigator's choice of standard therapy (eg, pembrolizumab, ipilimumab, or dacarbazine). PFS at 6 months was 31% with tebentafusp compared to 19% in the control group. This survival benefit marks a breakthrough in a disease historically associated with poor outcomes and limited responses to systemic treatments.[83]
Tebentafusp is associated with notable adverse effects, primarily immune-related toxicities. The most common adverse effects include cytokine release syndrome, which manifests as fever, hypotension, and fatigue, as well as dermatological-related reactions such as rash and pruritus. Despite these toxicities, most adverse effects are manageable with supportive care, and the significant survival benefit supports its continued use in this patient population.[83]
Tyrosine Kinase Inhibitors
Imatinib, a selective tyrosine kinase inhibitor, has demonstrated significant efficacy in treating dermatofibrosarcoma protuberans (DFSP), which is a rare cutaneous sarcoma characterized by the COL1A1–PDGFB fusion gene. This fusion leads to constitutive activation of platelet-derived growth factor receptor-beta (PDGFR-β), promoting uncontrolled tumor cell proliferation. By targeting PDGFR-β, imatinib inhibits this aberrant signaling pathway. In a systematic review, imatinib therapy resulted in complete responses in 5.2% of patients, partial responses in 55.2%, stable disease in 27.6%, and disease progression in 9.2% of cases.[84]
Imatinib has also demonstrated efficacy in treating certain soft tissue sarcomas, particularly gastrointestinal stromal tumors (GISTs), which frequently harbor activating mutations in the KIT or PDGFRA genes. This was the first targeted therapy to significantly improve clinical outcomes in GIST. In a landmark trial, imatinib treatment resulted in a median PFS exceeding 24 months in patients with metastatic GIST, with a partial response rate of approximately 50%.[85]
Additionally, imatinib has been investigated in other soft tissue sarcomas, such as tenosynovial giant cell tumor (TGCT), where overexpression of colony-stimulating factor-1 plays a pivotal role in pathogenesis. In a retrospective study, imatinib achieved a modest ORR of 19% in patients with TGCT.[86] However, its efficacy in non-GIST soft tissue sarcomas remains limited and appears more context-dependent than its effects in DFSP and GIST.
Imatinib is generally well-tolerated but requires monitoring for specific adverse effects. Common toxicities include fatigue, nausea, diarrhea, and periorbital edema. More severe adverse events, including hepatotoxicity, myelosuppression, and cardiotoxicity, are less frequent but warrant close observation during long-term use.[85]
Enhancing Healthcare Team Outcomes
Effective management of cutaneous malignancies with topical, oral, and injectable therapies requires a coordinated, patient-centered approach that leverages the unique skills and responsibilities of each healthcare team member. Physicians must evaluate tumor characteristics, including size, location, and histological subtype, to select the most appropriate treatment modality. Advanced practitioners, such as nurse practitioners and physician assistants, are crucial in treatment planning, monitoring response, and managing adverse effects. Nurses contribute by educating patients on proper application techniques, monitoring for adverse reactions, and ensuring adherence to treatment protocols. Pharmacists provide valuable support by counseling patients on potential drug interactions, preparing medications, and assisting with dose optimization. Together, these professionals must make strategic decisions that integrate clinical evidence, patient preferences, and safety considerations.
Effective interprofessional communication and care coordination are essential for ensuring seamless transitions across the continuum of care. Accurate documentation, timely referrals, and collaborative discussions help minimize errors and improve workflow efficiency. For instance, collaboration between dermatologists and pathologists supports accurate diagnosis, while coordination with pharmacists aids in managing systemic therapies and mitigating the risk of complications. Consistent communication enhances team performance, builds trust, and keeps the patient at the center of care. By working collaboratively in an integrated model, healthcare teams can provide safer, more effective, and compassionate care for individuals with cutaneous malignancies.
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