Metastatic squamous cell carcinoma represents a serious stage of skin cancer where the disease has spread beyond its original location, but with today’s treatment approaches—including surgery, radiation, and promising new therapies being tested in clinical trials—many patients have options that can help control the disease and improve quality of life.

Approaching Care When Cancer Has Spread

When squamous cell carcinoma moves beyond the skin where it first appeared, the focus of treatment shifts. The main goals become controlling the cancer’s growth, managing symptoms that affect daily life, and working to extend survival while maintaining the best possible quality of life. This differs from early-stage skin cancer, where doctors can often remove all traces of disease with a single procedure.^[5]

The approach to treating metastatic squamous cell carcinoma depends heavily on several important factors. Doctors consider where the cancer has spread—whether it remains near the original site or has traveled to distant organs like the lungs or liver. The number and size of tumors matter, as does the patient’s overall health and ability to tolerate different therapies. A person’s age, other medical conditions, and even their personal preferences about treatment intensity all play a role in deciding the best path forward.^[2]

Medical societies and cancer organizations have developed guidelines that doctors follow when treating this disease. These recommendations are based on years of research and clinical experience with thousands of patients. However, guidelines also recognize that each case is unique, and treatment plans are often tailored to the individual. Alongside established therapies that have been used for years, ongoing research continues to explore new approaches through clinical trials, offering hope for better outcomes in the future.^[6]

Standard Treatment Approaches

For metastatic squamous cell carcinoma that cannot be completely removed with surgery or controlled with radiation alone, doctors have traditionally turned to systemic treatments—medications that travel throughout the body to fight cancer wherever it may be. These treatments have evolved significantly over the past decades, moving from chemotherapy combinations to more targeted approaches.^[6]

Surgery and Radiation

Even when cancer has spread, surgery still plays an important role in certain situations. If the disease has moved to nearby lymph nodes but hasn’t traveled further, removing those affected nodes can be part of the treatment plan. This is particularly true for metastatic squamous neck cancer, where cancer cells are found in neck lymph nodes. Surgeons may perform a procedure called neck dissection, which removes lymph nodes and surrounding tissue where cancer has spread.^[2]

Radiation therapy uses high-energy beams to kill cancer cells or stop them from growing. For metastatic disease, radiation may be used after surgery to destroy any cancer cells that might remain in the area. It can also be the primary treatment when surgery isn’t possible due to the tumor’s location, size, or the patient’s overall health. Radiation is often combined with other treatments to improve effectiveness. The duration of radiation treatment varies, but patients typically receive treatments five days a week for several weeks.^[12]

Chemotherapy Combinations

Chemotherapy involves drugs that kill rapidly dividing cells, including cancer cells. For advanced squamous cell carcinoma, doctors have used various chemotherapy drugs over the years, though these treatments come with significant challenges. Cisplatin, a platinum-based drug, has been one of the most commonly used agents. It works by damaging the DNA inside cancer cells, preventing them from dividing and eventually causing them to die. Doctors often combine cisplatin with other drugs like fluorouracil (also called 5-FU), which interferes with cancer cell growth in a different way.^[10]

Other chemotherapy drugs that have been tested include bleomycin, which works by breaking DNA strands in cancer cells, and doxorubicin, which prevents cancer cells from replicating their genetic material. These drugs are typically given through an intravenous line over several hours, and treatment cycles repeat every few weeks. The duration of chemotherapy depends on how well the cancer responds and how well the patient tolerates the treatment.^[6]

However, chemotherapy for metastatic squamous cell carcinoma faces limitations. Clinical activity has been observed in some patients, but studies have generally been small and included mixed groups of patients, making it difficult to predict who will benefit most. Additionally, these drugs affect not only cancer cells but also healthy rapidly dividing cells throughout the body, leading to side effects that can significantly impact quality of life.^[10]

Side Effects of Traditional Treatments

Chemotherapy side effects occur because these drugs cannot distinguish between cancer cells and normal cells that divide frequently. Common side effects include nausea and vomiting, which can often be managed with anti-nausea medications. Hair loss occurs because chemotherapy affects hair follicle cells. Patients often experience fatigue that can be profound and affect their ability to carry out daily activities. The bone marrow, which produces blood cells, is particularly sensitive to chemotherapy, leading to low blood cell counts that increase the risk of infections, bleeding, and anemia.^[12]

Radiation therapy can cause skin changes in the treated area, similar to a sunburn that may peel or blister. Patients may experience fatigue that worsens as treatment continues. When radiation is directed at the head and neck area, it can cause mouth sores, difficulty swallowing, and changes in taste. These effects typically improve after treatment ends, though some may persist longer.^[12]

EGFR Inhibitors

A major advance in treating advanced squamous cell carcinoma came with the recognition that many of these tumors have high levels of a protein called epidermal growth factor receptor or EGFR. This protein sits on the surface of cells and, when activated, sends signals that tell cells to grow and divide. In cancer cells, EGFR is often overactive, driving uncontrolled growth. Researchers developed drugs specifically designed to block this receptor, potentially slowing or stopping cancer growth without affecting as many normal cells as traditional chemotherapy does.^[10]

Cetuximab is a type of drug called a monoclonal antibody that attaches to EGFR on the surface of cancer cells, blocking growth signals. It’s given through an intravenous infusion, typically once weekly. Studies have shown that cetuximab combined with chemotherapy can be more effective than chemotherapy alone for advanced squamous cell carcinoma. Side effects differ from traditional chemotherapy and commonly include skin rash, which can actually indicate that the drug is working. Other side effects may include infusion reactions during or shortly after receiving the medication.^[19]

Erlotinib and gefitinib are oral drugs that work differently—they block EGFR from the inside of the cell rather than from the outside. Patients take these as pills daily. Phase II clinical trials have shown preliminary evidence of activity against metastatic squamous cell carcinoma, though more research is needed to establish their exact role in treatment. These drugs can cause skin problems, diarrhea, and changes in liver function that doctors monitor with regular blood tests.^[10]

Immunotherapy: A New Frontier in Treatment

The field of immunotherapy has brought renewed hope to patients with advanced squamous cell carcinoma. Unlike chemotherapy, which directly attacks cancer cells, or targeted therapies that block specific proteins, immunotherapy works by helping the patient’s own immune system recognize and fight cancer. This represents a fundamental shift in how we approach cancer treatment.^[5]

How Immunotherapy Works

Under normal circumstances, the immune system patrols the body looking for abnormal cells, including cancer cells, and destroys them. However, cancer cells develop ways to hide from the immune system or turn it off. One way they do this is through proteins called checkpoint proteins. These proteins normally act as brakes on the immune system, preventing it from attacking healthy tissue. Cancer cells exploit these checkpoints to protect themselves from immune attack.^[5]

PD-1 inhibitors are drugs that block one of these checkpoint proteins called programmed death-1 (PD-1). When PD-1 on immune cells connects with its partner protein on cancer cells, it tells the immune cells to leave the cancer alone. By blocking this interaction, PD-1 inhibitors essentially “release the brakes” on the immune system, allowing immune cells to attack cancer more effectively.^[18]

Cemiplimab for Advanced Disease

Cemiplimab is a PD-1 inhibitor that has been specifically studied and approved for patients with advanced cutaneous squamous cell carcinoma. Clinical trials have demonstrated that cemiplimab can shrink tumors in patients whose cancer is not suitable for surgery or radiation, as well as in those whose cancer has spread to other parts of the body. The drug is given as an intravenous infusion every three weeks.^[18]

In clinical trials, cemiplimab showed response rates that were encouraging compared to historical outcomes with chemotherapy. Some patients experienced significant tumor shrinkage, while others achieved stable disease, meaning their cancer stopped growing. Perhaps most importantly, some patients who responded to treatment maintained those responses for extended periods, suggesting the possibility of durable disease control.^[18]

Side effects of cemiplimab differ significantly from chemotherapy. Because the drug activates the immune system, it can sometimes cause the immune system to attack normal tissues in the body, leading to what doctors call immune-related adverse events. These can affect various organs, including the lungs (causing pneumonitis or inflammation), the colon (causing colitis or inflammation), the liver (causing hepatitis), or hormone-producing glands like the thyroid. Fatigue is also common. While these side effects can be serious, they are often manageable with medications that suppress the immune response, such as corticosteroids. Doctors monitor patients closely during treatment with regular check-ups and blood tests.^[18]

Pembrolizumab as an Option

Pembrolizumab is another PD-1 inhibitor that has shown activity against advanced cutaneous squamous cell carcinoma. Like cemiplimab, it works by blocking the PD-1 checkpoint, allowing the immune system to fight cancer. Pembrolizumab is administered as an intravenous infusion, typically every three or six weeks depending on the dose used.^[18]

Clinical trials have demonstrated that pembrolizumab can produce tumor responses in patients with locally advanced or metastatic cutaneous squamous cell carcinoma. The safety profile is similar to cemiplimab, with immune-related side effects being the main concern. Patients receiving pembrolizumab require regular monitoring for signs of immune system overactivity affecting various organs.^[18]

Who Benefits from Immunotherapy

Not every patient responds to immunotherapy, and predicting who will benefit remains challenging. Researchers are studying various biomarkers—measurable characteristics of the tumor or the patient—that might help identify those most likely to respond. The amount of PD-1 or its partner protein PD-L1 expressed on tumor cells may play a role, though this relationship is complex and not perfectly predictive.^[18]

Immunotherapy has become a first-line treatment option for many patients with advanced cutaneous squamous cell carcinoma, particularly when the disease has spread extensively or when surgery and radiation are not viable options. The growing evidence supporting these drugs has changed the treatment landscape and given doctors and patients new reasons for optimism.^[5]

Clinical Trials and Emerging Therapies

Beyond the treatments already approved and in routine use, researchers continue to investigate new approaches through clinical trials. These studies are essential for advancing our understanding of how to treat metastatic squamous cell carcinoma more effectively. Clinical trials test new drugs, new combinations of existing drugs, and entirely novel approaches to fighting cancer.^[6]

Understanding Clinical Trial Phases

Clinical trials follow a structured pathway with different phases, each designed to answer specific questions. Phase I trials are the first studies in humans and primarily focus on safety. Researchers want to know what dose of a new drug can be given safely and what side effects occur. These trials usually involve small numbers of patients, often those whose cancer has not responded to other treatments.^[6]

Phase II trials build on Phase I findings by testing whether a drug actually works against a specific type of cancer. These studies look at how many patients’ tumors shrink or stop growing in response to treatment. Phase II trials enroll more patients than Phase I and provide the first real evidence of whether a new treatment shows promise. If a drug demonstrates encouraging activity in Phase II, it may move forward to Phase III testing.^[6]

Phase III trials are large, rigorous studies that compare a new treatment to the current standard treatment. These trials often enroll hundreds or even thousands of patients and are designed to definitively show whether the new approach is better than existing options. Patients are usually randomly assigned to receive either the new treatment or the standard treatment, ensuring a fair comparison. Results from Phase III trials provide the strongest evidence for whether a new treatment should become part of routine care.^[6]

Combination Immunotherapy Approaches

One area of active research involves combining different immunotherapy drugs. Scientists reason that blocking multiple checkpoints simultaneously might produce stronger immune responses against cancer. Trials are testing combinations of PD-1 inhibitors with drugs that block other checkpoints, such as CTLA-4. While early results have shown some promise, these combinations also tend to produce more immune-related side effects, so finding the right balance between effectiveness and tolerability is crucial.^[18]

Combining Immunotherapy with Other Treatments

Researchers are also exploring whether combining immunotherapy with chemotherapy, targeted therapy, or radiation might work better than any single approach alone. The rationale is that different treatments attack cancer through different mechanisms, and combining them might prevent cancer cells from developing resistance. Some studies are testing PD-1 inhibitors given together with EGFR inhibitors like cetuximab, hoping that the combination will be more effective than either drug alone.^[19]

Radiation therapy may also enhance the effectiveness of immunotherapy. When radiation destroys cancer cells, it releases tumor antigens—molecules that can help the immune system recognize cancer. This might make tumors more visible to the immune system and potentially improve responses to immunotherapy drugs. Clinical trials are investigating the optimal timing and sequencing of radiation with immunotherapy.^[6]

Novel Therapeutic Targets

Beyond checkpoint inhibitors and EGFR blockers, scientists are investigating entirely new targets for treatment. Some research focuses on other growth factor receptors that drive cancer cell proliferation. Others explore drugs that interfere with how cancer cells repair their DNA or how they obtain nutrients and oxygen. Each of these approaches is in various stages of development, from laboratory studies to early-phase clinical trials.^[6]

Where Clinical Trials Are Conducted

Clinical trials for metastatic squamous cell carcinoma are conducted at cancer centers and research hospitals around the world. In the United States, major cancer centers affiliated with universities and the National Cancer Institute conduct many trials. European countries also have active research programs studying new treatments. Some trials are international, enrolling patients from multiple countries to gather results more quickly.^[6]

Patient eligibility for clinical trials depends on many factors. Doctors consider the stage and characteristics of your cancer, what treatments you’ve already received, your overall health and organ function, and whether you have other medical conditions that might interfere with the study. Each trial has specific inclusion and exclusion criteria designed to ensure patient safety and produce reliable results.^[6]

Most common treatment methods

• Surgical Approaches
  • Excisional surgery to remove tumors and affected lymph nodes, particularly for locally advanced disease where complete removal is possible.^[5]
  • Neck dissection for metastatic squamous neck cancer, removing lymph nodes and surrounding tissue where cancer has spread.^[2]
  • Mohs surgery in select cases where preserving healthy tissue is critical, though less commonly used for metastatic disease.^[5]
• Radiation Therapy
  • External beam radiation as primary treatment when surgery is not possible due to tumor location, size, or patient health status.^[12]
  • Post-operative radiation to destroy remaining cancer cells after surgery and reduce recurrence risk.^[12]
  • Palliative radiation to relieve symptoms and improve quality of life in advanced cases.^[12]
• Chemotherapy
  • Cisplatin-based combinations, often with fluorouracil, for systemic treatment of metastatic disease.^[10]
  • Other agents including bleomycin and doxorubicin, used in various combinations depending on patient factors.^[10]
  • Combination regimens tailored to individual patient tolerance and disease characteristics.^[6]
• Targeted Therapy
  • Cetuximab, a monoclonal antibody that blocks EGFR, often combined with platinum-based chemotherapy.^[19]
  • Erlotinib and gefitinib, oral EGFR inhibitors showing preliminary activity in phase II trials.^[10]
• Immunotherapy
  • Cemiplimab, a PD-1 inhibitor approved for advanced cutaneous squamous cell carcinoma not suitable for surgery or radiation.^[18]
  • Pembrolizumab, another PD-1 inhibitor demonstrating tumor responses in locally advanced or metastatic disease.^[18]
  • Combination immunotherapy approaches under investigation in clinical trials.^[18]

Managing Life with Metastatic Disease

Living with metastatic squamous cell carcinoma involves more than just medical treatments. Patients often work with a multidisciplinary team that may include dermatologists, oncologists, surgeons, radiation oncologists, and other specialists. This team approach ensures that all aspects of the disease are addressed and that treatments are coordinated effectively.^[5]

Regular follow-up is essential even after treatment ends. Doctors schedule periodic examinations and imaging tests to monitor for any signs that cancer is returning or progressing. The frequency of these check-ups depends on the extent of disease and type of treatment received. Early detection of recurrence allows for prompt intervention, which may improve outcomes.^[4]

Managing side effects is an important part of care. Modern medicine offers many options for controlling treatment-related symptoms. Anti-nausea medications, pain relievers, medications to boost blood cell counts, and treatments for skin reactions can all help patients maintain their quality of life during therapy. Palliative care specialists focus specifically on symptom management and can provide valuable support throughout treatment.^[12]

The psychological impact of living with metastatic cancer should not be underestimated. Feelings of anxiety, fear, sadness, or anger are all normal responses to a serious diagnosis. Support groups, counseling, and connections with other patients facing similar challenges can provide emotional support. Many cancer centers offer resources to help patients and their families cope with the emotional aspects of cancer treatment.^[5]