Neoadjuvant therapy to reduce tumor size and preserve tissue
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PD-1 immunotherapy is best known as a treatment for SCC that surgery and radiation can no longer control. But the same drugs are also being used earlier — before an operation that is still possible, in order to make that operation smaller, safer, or less disfiguring.
This is called neoadjuvant therapy, from a Latin prefix meaning "new" combined with "adjuvant" (helping): a new, earlier use of a helping treatment. This article explains why it is used, what the clinical trials found, who is a candidate, what the treatment course looks like, and what happens whether or not the tumor shrinks.
Most SCC surgery happens without any systemic treatment first or after. Neoadjuvant immunotherapy is considered specifically when a tumor is technically resectable but the operation needed to remove it would be extensive — for example, a large tumor on the ear, nose, eyelid, or scalp where clearing it might mean removing an eye, a large piece of ear or nose cartilage, or a wide area of scalp and skull.
Giving a PD-1 inhibitor first, on the same drugs and biology described in immunotherapy for advanced SCC, can shrink the visible tumor and its microscopic edges before the surgeon operates. There are several potential advantages:
Neoadjuvant immunotherapy for cutaneous SCC has been studied in two notable trials, both using cemiplimab.
In a multicenter phase 2 trial, patients with stage II to IV, resectable cutaneous SCC received up to four doses of cemiplimab (about 12 weeks) before their planned surgery. Roughly 51% had a pathologic complete response — no viable cancer cells found anywhere in the tissue removed — and another 13% had a major pathologic response (only minimal residual disease), so about two-thirds had a complete or major pathologic response. On imaging, an objective response (meaningful shrinkage) was seen in about 68% of patients treated.
A later analysis of long-term outcomes in the head-and-neck patients from this trial found that those who had a pathologic complete or major response had no cancer recurrences at a median follow-up of over three years, with an overall 3-year survival around 90% for the full group.
A separate pilot phase 2 trial gave two doses of neoadjuvant PD-1/PD-L1 immunotherapy to patients with locoregionally advanced, resectable SCC of the head and neck before surgery. It found the approach was safe, did not meaningfully delay planned surgery, and produced a high rate of significant pathologic response — tumors that showed a strong immune response tended to have more immune cells already present before treatment started.
Both trials point the same direction: giving immunotherapy first, in patients whose tumors are still operable, produces a high rate of major tumor response without making surgery riskier or significantly delayed.
After surgery, a pathologist examines the entire removed specimen under the microscope and grades how much, if any, live tumor remains compared with dead or scarred tissue:
A pCR or MPR is a strong, reassuring sign; imaging response before surgery is a helpful preview but does not always match what the pathologist finds afterward, which is one reason surgery is not skipped.
Neoadjuvant immunotherapy is considered for a specific situation, decided by a multidisciplinary tumor board of dermatology, surgical oncology or head and neck surgery, medical oncology, and radiation oncology:
Side effects during the neoadjuvant course are the same immune-related reactions seen with immunotherapy generally — see how the side effects of immunotherapy are managed — and are monitored closely since surgery is still scheduled ahead.
Not every tumor responds. If imaging during the neoadjuvant course shows the cancer is growing rather than shrinking, the plan shifts to surgery (or the originally planned treatment) without delay, and the case is reviewed for other systemic options.
Even when the response is excellent — including cases where the tumor is no longer visible on imaging or exam — surgery is still performed outside of a clinical trial. A pCR on imaging does not guarantee a pCR under the microscope, and leaving even a small amount of residual cancer in place would risk recurrence. Some trials are now studying whether truly exceptional responders can safely avoid surgery, but that is investigational and not yet standard practice.
Immunotherapy can also be given after surgery — called adjuvant therapy — for tumors that were successfully removed but carry a high risk of coming back, based on features covered in what makes an SCC "high-risk" or evidence of perineural invasion. Neoadjuvant and adjuvant immunotherapy answer different questions — shrinking a tumor before an operation versus lowering the odds of recurrence after one — and a person is generally offered one or the other, not both, depending on how their case unfolds at the tumor board.
Giving a PD-1 inhibitor before surgery, rather than only after surgery and radiation have failed, is one of the newer strategies for locally advanced SCC that is still operable but would otherwise require an extensive procedure. In the trials so far, roughly half of treated patients had no detectable cancer left in the tissue removed, and responders have gone years without recurrence.
The tradeoff is time — a several-month course before the operation everyone already expected to happen — and, for some patients, a health condition such as an organ transplant that makes immunotherapy of any kind a more complicated decision, discussed in SCC in transplant recipients and immunosuppressed patients.
Disclaimer: This article is for educational purposes only and not a substitute for professional medical advice. Always consult a qualified dermatologist or oncologist about your personal diagnosis and treatment plan.
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