MDT Review
Confirm cutaneous origin, extent of disease, resectability, radiation feasibility, immune risk, transplant/immunosuppression status, and treatment intent through MDT review. MDT review should include dermatology, surgical oncology or Mohs surgery, head and neck surgery when relevant, radiation oncology, medical oncology, pathology, radiology, and transplant/immunology teams when relevant.
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Special population: transplant, immunosuppression, or active autoimmune disease
Use individualized risk–benefit assessment with oncology and the relevant transplant or organ specialist. Checkpoint inhibition may increase the risk of allograft rejection or autoimmune-disease exacerbation. Consider alternative local or systemic strategies and clinical-trial participation when appropriate. Selected kidney-transplant recipients have received cemiplimab with protocolized modification of immunosuppression, but these limited data should not be generalized to all transplant types or immunosuppressive regimens. Consider Clinical Trials for immunosuppressed patients: Study of Intralesional Cemiplimab in Adult Patients With Early Stage Cutaneous Squamous Cell Carcinoma A Randomized Phase II Study of Amivantamab (JNJ-61186372) and Hyaluronidase (rHuPH20) Versus Cetuximab in Immunocompromised Participants With Recurrent Inoperable or Metastatic Cutaneous Squamous Cell Carcinoma
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Resectability and Curative Local-Therapy Assessment
Is the disease clearly resectable, borderline resectable with potentially morbid surgery, or unresectable / not amenable to curative local therapy?
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Borderline Resectable / Function-Threatening Surgery
For disease that is technically resectable but would require morbid, disfiguring, function-threatening, or organ-threatening surgery, discuss neoadjuvant immunotherapy in MDT. Best fit: - Resectable stage II–IV disease where surgery is feasible but high morbidity is expected. - Head and neck cSCC where surgery may compromise function, cosmesis, eye/ear/nose structures, facial nerve, swallowing, or quality of life. - Patient is fit for immunotherapy and can be monitored closely. - No urgent need for immediate definitive local control. Important caveat: Neoadjuvant immunotherapy may downstage disease and improve surgical feasibility, but omission of surgery should not be presented as routine standard care outside clinical trial or expert MDT context.
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MDT-selected neoadjuvant cemiplimab approach
Consider neoadjuvant cemiplimab in selected patients with resectable cSCC when standard surgery would cause major functional, cosmetic, or organ morbidity. Plan definitive surgery before treatment and reassess resectability after the neoadjuvant course. Routine omission of surgery after response is not established and should be considered only in a clinical trial or an exceptional expert-MDT setting.
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Reassess after neoadjuvant cemiplimab
Reassess clinical and radiographic response, resectability, anticipated surgical morbidity, and the feasibility of definitive local treatment through MDT review.
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Unresectable / Not a Candidate for Curative RT
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Approved checkpoint inhibitor options
FDA-approved checkpoint inhibitor options for adults with locally advanced or metastatic cSCC who are not candidates for curative surgery or curative radiation: Approved anti–PD-1 options: • Cemiplimab-rwlc. • Pembrolizumab. Approved anti–PD-L1 option: • Cosibelimab-ipdl. Select treatment according to the labeled indication, immune-risk profile, toxicity considerations, access, and patient preference.
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Initiate checkpoint inhibitor therapy + safety monitoring
Baseline assessment and ongoing monitoring/management of immune-related adverse events (including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, myocarditis, neurologic toxicities) are supported by major society guidance for checkpoint inhibitors and are applicable across PD-1/PD-L1 agents.
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Assess response, clinical benefit, and treatment tolerance
Is there meaningful clinical benefit with acceptable toxicity, or confirmed progression / unacceptable toxicity? Assess: Clinical response and symptom improvement. Radiographic response according to disease extent and treatment plan. Functional outcome and quality of life. Treatment tolerance and immune-related toxicity. Whether stable disease represents meaningful ongoing clinical benefit. Whether apparent early progression could represent pseudoprogression in an otherwise clinically stable patient. Whether local therapy could address symptomatic, threatening, or oligoprogressive disease. Do not change treatment automatically for an isolated early imaging change without reviewing symptoms, disease tempo, confirmatory imaging when appropriate, and MDT context.
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Clearly Resectable