AJMC®: How do you assess whether a basal cell carcinoma (BCC) has potential to become advanced? At the point of diagnosis, what treatment options do you consider?
Schlesinger: There are certain things that we look at when it comes to whether a BCC is more advanced. One question is: Is the tumor of a large size? Another is: Is the tumor in an area that is close to a critical structure of the body? Is it near the eye? Will the removal of that tumor cause significant morbidity to the patient? Tumors may involve removing part of a nose, part of an ear, or another structure. Large or more advanced-appearing tumors may be ulcerated or show advanced features. BCCs that are recurrent and have been treated before with surgery, radiation, or possibly even other chemotherapeutic agents are more advanced and riskier. Other tumors display advanced features that may only be detected during removal, such as perineural invasion: Involving a nerve, especially a main nerve or a nerve greater than 0.1 mm, also increases the risk of the BCC.
We also think about tumor types histologically. Tumors of the morpheaform or sclerosing BCC pattern as seen under the microscope—and ulcerated BCC—are [riskier] because their growth pattern is not uniform; they may invade tissue in ways that are harder to detect. Collision tumors are those in which you have a squamous cell carcinoma and BCC in the same specimen. Those are also higher risk for progression: local spread and/or in transit metastasis, which is local lymphatic spread. Basal cell carcinomas spread locally most of the time. They usually spread by invading the tissue surrounding the tumor, but have potential for metastases as well.
Those are the first things you think of when you look at a tumor and you want to decide if it’s advanced. You think about those risk factors. You also consider if a patient might be immunocompromised. Do they have factors that may allow that tumor to grow more quickly? Those are all first considerations that you would think about. But often, you first consider location, size, and the risk of surgery: What would happen to that patient if you were to remove the tumor with standard technique Mohs surgery or extirpation of any kind?
AJMC®: What is the importance of multidisciplinary care in treating of BCC?
Schlesinger: The multidisciplinary team, or MDT, is an important part of the care, and the patient is at its center. Depending on the tumor and its level of advancement, different team members may be involved. There is a major decision to be made between surgery and chemotherapy or surgery and radiation or [other options]. You may want to involve other specialties. If you’re a dermatologist, that may [include] Mohs surgery, maybe medical oncology, surgical oncology, radiation oncology. It may be general surgery or head and neck oncology or head and neck surgery. A pathologist may also be involved.
The MDT is important because when these tumors become large or more advanced, you do run into additional risk factors that one specialty may not be able to manage. There could be a structural risk factor. Maybe there is an ophthalmological concern with an eye or an ear, nose, and throat concern with an advanced tumor of the ear canal. Maybe neurology or neurosurgery should be involved. I think it’s in the patient’s best interest that they receive a multidisciplinary specialty approach. This is common in major academic centers, but an MDT may be hard to put together within a community physician group. Nevertheless, the patient should have the benefit of the different groups and opinions throughout their care and treatment.
AJMC®: When do you decide that you need an MDT or another physician?
Schlesinger: When a patient’s tumor is at a point at which you think curative surgery or curative radiation is not possible, or if it’s something you either can’t treat yourself or [you] refer to a single place to be treated, you look into other options. In the community, MDT formation is often very loosely organized. There may be a text message or a phone call between yourself and another physician. There may be referral to another physician to take over the patient’s care and use another team. Or it may be that you refer to different physicians and you manage that patient’s care throughout the whole process. It looks different to different people and is based on the community you’re in, who you’re comfortable working with, and who you have available. Some people don’t have all these physicians available. They have to refer to a major city or academic center and maybe into an existing MDT. However, if they’re in a robust private medical care community, they may be able to put together an MDT and be its leader.
Communication becomes an issue with [the need to] pass around records and notes and information about the patient with their privacy in mind. But in private practice, MDT formation often starts with a phone call or text message to another doctor to get their opinion about what’s going on and then maybe have the patient seen. Also, many of the major academic centers where we train have multidisciplinary tumor boards where those patients are presented on a regular basis to a group. Some academic centers engage us community practitioners in grand rounds. If there is a local academic center that you’re affiliated with, sometimes turning a patient into the grand rounds as a first step gets exposure to multiple specialties at once. Some opinions come out and you can then have multidisciplinary care.
AJMC®: What role do Hedgehog inhibitors (HHIs) and immune checkpoint inhibitors (ICIs) have in the treatment of BCC? How do adverse effects (AEs) factor in?
Schlesinger: It’s exciting to have these new technologies available to our patients. ICIs pick up where Hedgehog pathways leave off. HHIs are great [for treating] patients with large tumors, multiple tumors, and some very advanced tumors. However, they require long-term treatment, and we don’t really know what the end point is. They have their AEs, which are [often] manageable with dose modification and/or additional treatments.
Checkpoint inhibition is another excellent modality. It is also very powerful. It’s a different mechanism of action: We’re activating the patient’s immune system to target tumors, to “uncloak” them so they can be seen by the circulating T cells and create a cytotoxic response within and around the tumor to help destroy it. ICIs take [efficacy] to another level. However, with ICIs, you have a greater depth and breadth of AEs that can occur. AEs are very common with ICIs, though most of the time not severe. We notice that ICI AEs can affect almost any organ system in the body, whereas HHI AEs are quite limited to gastrointestinal and neurological systems. HHIs can have other AEs, but because HHIs are focused on the Hedgehog pathway mutations that are occurring within the tumor itself, the AEs are limited to certain body systems. Because ICIs activate the body’s immune system generally as well as at the tumor site, you can have a greater depth and breadth of AEs. You’re a little more likely to have a more severe event with an ICI, but you’re also able to treat tumors that are more advanced as well as metastatic.
You have approvals of HHIs and ICIs for the metastatic groups. I think these therapies go hand-in-hand. They would be used independently of one another, but as some trials have shown, the patients who are treated with checkpoint inhibitors had already been treated with HHIs and either didn’t respond, had progression, and/or had intolerable AEs. For BCCs, I wouldn’t say that ICIs are first-line therapy, although it can be considered first line in many cases. Either one can be used depending on the patient’s risk factors. If you are going to use ICIs, you have to be able to manage the AEs effectively and early. But most patients do well and have manageable AEs.
A good safety profile is important. Cemiplimab is currently the only ICI approved for BCC. I think it [will be] reserved for the more severe BCC, though. The definition of “not amenable to curative surgery” or “not amenable to curative radiation” means different things to different people. Maybe we use cemiplimab for patients with multiple tumors who have surgical fatigue. Maybe we won’t need to take their eye out to get the tumor out. Maybe they have had 15 or 20 surgeries and prefer to try something that is nonsurgical. There may be other things to think about.
AJMC®: An evolving treatment spectrum for BCC includes these nonsurgical options. What are some of the managed care considerations you would have for the changing landscape?
Schlesinger: From a managed care perspective, when you’re talking about treating larger tumors, a surgical approach also needs extensive care. You’re also looking at care with a lot of associated morbidities. If you’re doing a large surgery followed by multidisciplinary reconstruction—for example, you have a tumor in the mid-face or that can be recurrent, which is not uncommon—that tumor may involve several specialties. It may involve head and neck oncology or surgical oncology. It may involve more surgery—nose and throat—followed by radiation therapy. That care could run in the millions. In such cases, the ICI might be a more cost-effective option than the surgery and carry less morbidity for the patient especially as we learn and achieve better outcomes with ICIs over time.
Another case, from a managed care standpoint, is when there are multiple tumors. A patient may be coming in for multiple Mohs surgeries and reconstruction, and [those costs] can add up as well—not only for the health care system but also from [the standpoint of] a patient’s decreased productivity. Every Mohs surgery requires the patient to rest and be off work. That costs money to employers and to the patient. And so all of that recovery time can become an issue especially when there are multiple tumors or when there’s a very large tumor requiring a large reconstruction. It can be good to reach for a systemic therapy when there’s a large number of tumors that can be addressed with one therapy as opposed to repeated surgical intervention. I think from a managed care perspective, systemic therapy stands up there with the rest.
Certainly, Mohs surgery is the gold standard when it comes to tumors that are amenable to it that can have a reasonable chance of being completely removed with clear margins. That would be the original goal. It is very important if you can get clear margins because you have higher risk when you don’t get clear margins. Salvage radiation—where we’re going in to, say, radiate a tumor that we know is not clear—can have a poor outcome. Getting a clear margin is important if you’re going to be doing surgery. A systemic route may be another very viable option, even from a cost standpoint.
AJMC®: We’ve seen more data for both HHIs and ICIs like cemiplimab. Are there new horizons for their potential usability or for systemic therapy in general? What more would you like to see?
Schlesinger: There’s a lot to learn, and I think we’re just starting. These are very new therapies. The efficacy for ICIs with BCC being in the 20% to 30% range is good, but there’s a lot to be developed for the tumors that fail to respond. What do you do with patients who have intolerable AEs? Can we manage those? Are there other add-on medications? Are there new targets? Already, companies are looking into how to improve the efficacy and efficiency of our existing ICI therapies by adding on other medications to eradicate the tumor or reduce its size. I think we’ll also see other targets.
This is a rapidly moving time as you can see from the development of the COVID-19 vaccines. With current technology, we can go from target to commercial much more quickly. As we learn more about what receptors are available on tumors, we’ll be able to develop new targets or enhance the benefits. This is already happening. The research world is already looking into ways to make these drugs more effective: administering them in different ways, for instance. There’s a lot of advancement. We just want to see it continued to improve the efficacy of medications and safety. Our holy grail is 100% effective with no AEs. That is not achievable in some cases. However, the more we can get increased efficacy with decreased AEs, the more efficient we can consider our treatments from both health care cost and patient morbidity standpoints.
AJMC®: Given the recent advances, what does the future of BCC treatment look like? What are your key takeaways when it comes to optimizing patient care?
Schlesinger: The main thing to think about is the education of physicians and getting the word out about these treatments, which are still very new. Though there are many opportunities for patients to access them, these medications come through their physicians. The more we can get physicians educated about these new technologies and their availability in therapies, the better. Oftentimes a lot of these patients end up with these types of advanced tumors and are unfortunately underserved or subject to issues with health care disparity. It’s a population that oftentimes can benefit highly from these drugs: The patients who are coming in with the advanced tumors from the outset, in many cases, don’t have access to care and are coming in only when their tumors are already in an advanced stage. We can get even down to the primary care physicians to be aware that these technologies are there, so that these patients can be channeled into treatment. I think physician education is a key consideration.