Squamous cell carcinoma (SCC) originates in the squamous cells found on the surface of the skin and in the lining of hollow organs. While most cases are treated successfully with local therapies, a small percentage progress to an advanced stage. Advanced SCC means the disease has grown aggressively, invaded surrounding tissues, or spread to distant parts of the body. Understanding systemic treatments is important for patients navigating this challenging diagnosis.
Understanding Advanced Squamous Cell Carcinoma
Advanced squamous cell carcinoma (ASCC) describes cancer that has progressed beyond the scope of localized treatments like surgery or radiation. This progression involves locally advanced disease, which has grown deeply into surrounding structures, or metastatic disease, which has spread to distant sites. Most ASCC cases arise from the skin (cutaneous SCC or cSCC), often in sun-exposed areas, but SCC can also originate in the linings of the mouth, throat, or lungs.
Staging helps define this advanced state. Stage III indicates that the tumor has grown significantly or has spread to regional lymph nodes, but not to distant organs. Stage IV represents the most advanced classification, signifying that the cancer has metastasized to distant sites, such as the lungs, liver, or bone. Locally advanced tumors may show high-risk features like perineural invasion, where cancer cells track along a nerve, making the cancer more difficult to control locally.
Advanced SCC requires a shift from curative local management to systemic therapy aimed at controlling the widespread disease. The prognosis for ASCC is less favorable than for early-stage disease, especially once the cancer has spread beyond the regional lymph nodes. Systemic treatment affects the entire body and is necessary when the cancer burden is too extensive for localized interventions. This approach aims to shrink tumors and extend survival, often in a palliative setting.
Systemic Treatment Approaches
Systemic treatment is the primary strategy for managing advanced SCC when local therapies are insufficient. This approach uses medications that circulate throughout the body, targeting cancer cells wherever they reside. Systemic options include immunotherapy, targeted therapy, and traditional chemotherapy, often used sequentially or in combination. The selection of a specific regimen depends on the tumor’s origin, its molecular characteristics, and the patient’s overall health status.
Immunotherapy
Immunotherapy has improved treatment for advanced SCC, particularly cutaneous SCC (cSCC), by leveraging the body’s own immune system to fight the cancer. These treatments primarily involve immune checkpoint inhibitors, which block proteins that cancer cells use to evade detection by the immune system’s T-cells. The most common targets are the Programmed Death-1 (PD-1) protein and its ligand, PD-L1.
PD-1 inhibitors, such as cemiplimab and pembrolizumab, have received regulatory approval for treating locally advanced or metastatic cSCC that is not curable by surgery or radiation. These monoclonal antibodies work by “releasing the brakes” on the T-cells, allowing them to recognize and attack the cancer cells. Clinical trials for cemiplimab in advanced cSCC have shown overall response rates in the range of 41% to 50%.
The effectiveness of immunotherapy in SCC is partly attributed to the tumors often having a high mutational burden, especially in sun-exposed skin cancers. A high number of mutations makes the cancer cells appear more foreign to the immune system, making them more susceptible to checkpoint blockade. Immunotherapy has become a first-line standard of care for many patients with advanced SCC due to its promising response rates and durable disease control.
Targeted Therapy
Targeted therapies focus on specific molecules or pathways within cancer cells that drive their growth and survival. In some forms of SCC, the Epidermal Growth Factor Receptor (EGFR) signaling pathway is frequently overactive, promoting cell proliferation and survival. EGFR inhibitors represent a class of targeted agents that were among the earliest systemic options for advanced SCC.
Monoclonal antibodies like cetuximab bind to the EGFR receptor on the surface of cancer cells, preventing growth signals from reaching the cell interior. Clinical studies involving EGFR inhibitors in advanced cSCC have demonstrated overall response rates ranging from 15% to 31%. Their role has been partially supplanted by the superior efficacy of PD-1 inhibitors in many settings.
The use of targeted therapy often requires genetic testing of the tumor to confirm the presence of the specific molecular target. Research continues to identify new molecular targets to expand the range of precise treatments available. For example, other targeted approaches, like those for the Hedgehog pathway, are relevant for basal cell carcinoma but are not used for advanced SCC.
Chemotherapy
Before modern immunotherapy, chemotherapy was the mainstay of systemic treatment for advanced SCC, and it still holds a role in certain circumstances. These agents, such as cisplatin and 5-fluorouracil (5-FU), work by directly destroying rapidly dividing cells, including cancer cells. Chemotherapy is sometimes used in combination with radiation therapy for locally advanced disease, or as a palliative option for metastatic disease.
Platinum-based regimens have been the most commonly studied in SCC, showing overall response rates of around 34% in some trials. However, chemotherapy is associated with a broader range of side effects and is often poorly tolerated by elderly or less healthy patients, a common demographic for cSCC. Its use in advanced SCC is reserved for situations where other, more tolerable options have failed or are not appropriate for the patient’s specific cancer type.
Clinical Trials
Clinical trials are an important avenue for patients with advanced SCC, offering access to novel treatments. These trials investigate new drugs, combination therapies, or alternative uses for existing treatments, such as different immunotherapy combinations. Participation provides the opportunity to receive cutting-edge care when standard treatments have been exhausted or when the patient’s disease is highly resistant.
Prognosis and Supportive Care
The prognosis for advanced SCC varies significantly based on the tumor’s site of origin, the extent of metastasis, and the patient’s general health status. While early-stage SCC has a high five-year survival rate, the prognosis drops substantially once the disease has spread to distant organs. Tumors arising from mucosal surfaces, such as in the head and neck region, often carry a worse prognosis than those originating from the skin.
Factors that negatively influence prognosis include immunosuppression, large tumor size, and the presence of high-risk features like deep invasion or spread to multiple lymph nodes. A robust response to systemic treatment, especially immunotherapy, can lead to durable disease control and a more favorable outcome. The introduction of modern systemic treatments has improved survival expectations for many patients with ASCC.
Supportive care is an integral part of managing advanced SCC and focuses on maintaining a high quality of life alongside cancer treatment. It is provided throughout the course of the illness to address symptoms and treatment side effects. Pain control, management of nausea, and nutritional support are important components, especially as advanced tumors can interfere with normal bodily functions.
The multidisciplinary team managing ASCC will include palliative care specialists, who work to relieve suffering and provide emotional and spiritual support for the patient and their family. Following systemic therapy, monitoring is necessary due to the possibility of recurrence or the development of new skin cancers. Follow-up schedules involve physical examinations and imaging tests to monitor for any signs of disease progression or new lesions.