What are the treatment options for a patient with metastatic skin cancer?

Treatment of Metastatic Skin Cancer

For metastatic cutaneous squamous cell carcinoma (cSCC), systemic immunotherapy with PD-1 inhibitors (pembrolizumab or cemiplimab) is the first-line treatment, while metastatic basal cell carcinoma should be treated with smoothened inhibitors (vismodegib or sonidegib), and metastatic melanoma requires immune checkpoint inhibitors or targeted therapy based on molecular profiling. 1, 2

Metastatic Cutaneous Squamous Cell Carcinoma (cSCC)

First-Line Systemic Therapy

• Pembrolizumab is FDA-approved for recurrent or metastatic cSCC that is not curable by surgery or radiation, representing the strongest evidence-based option 2
• Cemiplimab (another PD-1 inhibitor) has demonstrated efficacy in advanced unresectable cSCC and should be considered as an alternative first-line agent 1, 3
• These immunotherapies have largely replaced traditional chemotherapy as the standard of care for advanced disease 3

Alternative Systemic Options When Immunotherapy Fails or Is Contraindicated

• Epidermal growth factor receptor (EGFR) inhibitors such as cetuximab or panitumumab have demonstrated efficacy in phase II trials for patients with advanced unresectable cSCC 1
• Platinum-based chemotherapy (cisplatin alone or combined with 5-fluorouracil) shows some activity but has limited supporting evidence and does not improve overall survival consistently 1
• The EXTREME regimen (platinum-based chemotherapy combined with cetuximab) achieves median survival of 10-14 months with overall response rates of 36-44% 4

Locoregional Disease Management

• Surgical resection with possible lymph node dissection remains the primary treatment for operable regional lymph node metastases 1
• Adjuvant radiation therapy should be considered after surgery, particularly for patients with multiple involved lymph nodes or extracapsular extension 1
• For inoperable lymph node metastases, combination chemoradiation therapy is recommended 1, 4

Critical Management Considerations for cSCC

• Multidisciplinary consultation involving medical oncology, radiation oncology, and surgical oncology is mandatory given the complexity and rarity of metastatic cSCC 1, 4
• In immunosuppressed patients (particularly solid organ transplant recipients), reduce doses of calcineurin inhibitors (cyclosporine, tacrolimus) and antimetabolites (azathioprine) in favor of mTOR inhibitors (sirolimus) when appropriate 1, 4
• Best supportive and palliative care should be integrated from diagnosis to optimize symptom management and quality of life 1, 4

Metastatic Basal Cell Carcinoma (BCC)

First-Line Systemic Therapy

• Vismodegib (smoothened inhibitor) is FDA-approved and represents the standard first-line systemic therapy for metastatic BCC, with an objective response rate of 33% in metastatic disease 1
• Sonidegib is an alternative smoothened inhibitor with comparable efficacy 1
• These hedgehog pathway inhibitors have transformed the treatment landscape, as no approved therapy existed prior to 2012 1

Alternative Options

• When smoothened inhibitors are not feasible, platinum-based chemotherapy may be considered, though data are limited to case reports and series 1
• For metastatic disease limited to regional lymph nodes, surgery and/or radiation therapy remain appropriate when possible 1

Important Toxicity Considerations

• Drug toxicity with smoothened inhibitors is substantial: 25% of patients experience serious adverse events 1
• Common adverse events include muscle spasms, arthralgias, alopecia, dysgeusia, and weight loss 1
• Approximately 12-36% of patients discontinue treatment due to adverse events 1

Metastatic Melanoma

Treatment Approach

• There is no single standard therapy for metastatic melanoma; treatment must be adapted according to number of lesions, rate of disease progression, and patient performance status 1
• Immune checkpoint inhibitors (particularly PD-1 inhibitors like pembrolizumab) are now standard for many patients with metastatic melanoma 2
• Targeted therapy based on molecular profiling (e.g., BRAF/MEK inhibitors for BRAF-mutant melanoma) represents another key treatment modality 5
• Conventional palliative chemotherapy with dacarbazine remains an option, though polychemotherapy has not been shown superior to dacarbazine alone for survival 1

Surgical Considerations

• Surgical excision of isolated local recurrences or slowly developing single metastases may be considered, as this represents one of the few potentially curative approaches 1
• Resection of in-transit metastases can provide meaningful benefit in selected patients 1

Metastatic Merkel Cell Carcinoma (MCC)

Treatment Strategy

• Pembrolizumab is FDA-approved for recurrent locally advanced or metastatic MCC in both adult and pediatric patients 2
• For palpable nodal metastases, lymph node dissection is the preferred treatment 1
• Radiation therapy as sole treatment for macroscopic nodal disease should only be considered in patients who are poor surgical candidates or refuse surgery 1

Universal Principles Across All Metastatic Skin Cancers

Surveillance and Follow-Up

• For patients with regional disease, perform history and physical examination every 1-3 months for year 1, then every 2-4 months for year 2, then every 4-6 months for years 3-5, then every 6-12 months annually for life 1
• Clinical assessment must include complete skin examination and regional lymph node examination 1
• Imaging studies (CT or PET/CT) may be performed every 6-12 months for high-risk patients, even in the absence of symptoms 1

Common Pitfalls to Avoid

• Do not delay multidisciplinary consultation—the complexity of metastatic skin cancer requires coordinated care planning from diagnosis 1, 4
• Do not overlook the primary tumor site when treating metastatic disease, as locoregional control may still be achievable and impacts survival 4
• Do not initiate systemic therapy without considering the patient's immunosuppression status, as this significantly impacts treatment selection and prognosis 1, 4
• Do not forget to integrate palliative care early—approximately 70% of patients with metastatic cSCC die from their disease, making symptom management and quality of life paramount 6, 7

Clinical Trial Participation

• Clinical trials are strongly recommended for all patients with metastatic skin cancer, as they represent the best management approach and may provide access to novel therapies 1