Advanced/Metastatic cSCC Treatment Options

Insights From: Robert L. Ferris, MD, PhD, UPMC Hillman Cancer Center; Anna C. Pavlick, DO, NYU Langone Hospitals; Todd E. Schlesinger, MD, FAAD, FASMS, Dermatology & Laser Center of Charleston


Robert L. Ferris, MD, PhD: Primary treatment options for advanced squamous cell carcinoma of the skin have been surgery when possible. The goals of surgery are not only to obtain clear margins but also to assess the nodal basin. In addition, as I pointed out, many of the high-risk features of advanced squamous cell carcinoma of the skin come from the pathology specimen that the surgeon provides. And so perineural invasion, a differentiation status, margins, thickness, 6 mm greater or less than, these are features that we really only get by the surgical specimen. And so, we’ve tended to bias our upfront therapy to incorporate surgery where possible.

Radiation therapy is often used in the adjuvant setting when margins are questionable or when an R0 resection cannot be obtained. Chemotherapy has been relatively underutilized for squamous cell carcinoma, although it appears to have some efficacy, much as it does for squamous cell carcinoma of other regions such as the mouth and throat. We’ve also since 2006, the EGFR-specific antibody, cetuximab, which was FDA approved for mucosal squamous cell carcinomas, has begun to be used for advanced and in some cases, unresectable squamous cell carcinoma of the skin. So, the EGFR inhibitor, cetuximab, is a systemic therapy. Often, it’s combined with local radiation therapy, whether surgery can be done or not, whether it’s in a non-surgical palliative situation, or in the postoperative adjuvant to reduce rates of locoregional recurrence.

And then most recently, FDA approval for the anti–PD-1 antibody, the immunotherapy, cemiplimab, which targets the inhibitory PD-1 receptor in the immune system and reactivates the immune system against cancer. And PD-1 inhibitors have been FDA approved for 7 or 8 other cancers, and so adding the PD-1 inhibitor, cemiplimab for aggressive skin cancers, either unresectable locally advanced or for metastatic disease, has been a new transformation and an additional modality in the armamentarium for the oncologist.

Todd E. Schlesinger, MD, FAAD, FASMS: So, when considering excision versus Mohs surgery in our practice, we follow the well-established criteria. So, we’re looking at tumor location again, which is following the guidelines that are set [stumbled], have been set forth—tumors on the central face, tumors on the ears, tumors, for example, on the genital areas, or on the hands and feet are all candidates for Mohs surgery. If a tumor is recurrent, the tumor has actually come back in the same location, it’s another thing that will throw us over to the Mohs surgery side.

If a tumor is poorly differentiated, for example, is another reason why the tumor, we prefer to do Mohs surgery in cases such as this. Also, in tumors that are excessively large are going to definitely be treated with Mohs surgery. And the patient’s status is another, you know, another factor. So, if a patient is immunocompromised, again, that seems to play a big role in whether we’re going to perform Mohs surgery. Because in someone who’s immunocompromised, a patient who doesn’t have the immune system to handle any possible micrometastases or satellite lesions that can be coming, we want to make sure that we have a very clear margin and give them the highest chance for cure.

Robert L. Ferris, MD, PhD: The risk of distant metastasis is relatively low in cutaneous squamous cell carcinoma in the general population. If we looked at the rates in those with chronic immunosuppression, either due to chronic lymphocytic leukemia or to pharmacologic immunosuppression, that rate goes up 50- to 100-fold. And so, the risk of aggressive disease and metastatic disease, and that can be either dermal metastasis, which we think is equivalent to a distal, distant metastasis to an unrelated organ, that we need to encompass all of that. And I think our numbers are probably not as accurate as they could be because only recently in the past year or two have major centers like ours really coalesced a group who does appropriate distant metastasis imaging and follows these patients in a multidisciplinary setting. So, although it’s the minority, it’s probably 5% or less. When you get into higher risk groups, that number actually increases, and, in fact, aggressive, metastatic, unresectable skin cancer is the single greatest cause of mortality in the organ transplant population. It’s not the failure of the organ, it’s their uncontrolled skin cancer.

Todd E. Schlesinger, MD, FAAD, FASMS: What percentage of patients are curable with surgery? So, we speak more of curing lesions than of curing patients. Looking at an individual lesion, we make a decision on a case-by-case basis of whether we think that lesion is curable via surgery, or whether other modalities are necessary. So, we see the range of small tumors that are easily excised, and cured quite easily; or you know surgery, a tumor that we can treat with Mohs surgery and get a clear margin on that would give us a high rate of confidence in our ability to cure that particular lesion. Of course, you never know whether that lesion could recur in the future, so you always have to follow the patients quite carefully over time. So, cure is a really hard word to, a really hard word to define. And so, I can only answer that question with, it depends.

Robert L. Ferris, MD, PhD: The number of patients who are curable with advanced cutaneous squamous cell carcinoma I think is increasing. We’ve begun to understand better how to use EGFR inhibitors like cetuximab. Our radiation oncologists have gotten better at perineural invasion and radiating the pathways of spread along these major nerves, particularly in the head and neck when it’s cranial nerves going to the skull base. And I also think that the new FDA approval of immunotherapy is going to add a real survival advantage because of the immune memory that the PD-1 inhibitors provide. Unlike the biologics and radiation therapy where the benefit tends to go away when the treatment stops, the anti–PD-1 therapies have durability and, in fact, can give long-term, in some cases, cure.

Transcript Edited for Clarity
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