Updates in the Management of High-Risk Cutaneous Squamous Cell Carcinoma

Cancer staging, appropriate imaging, and treatment/follow-up are the keystones to delivering the best care for high-risk patients with cutaneous squamous cell carcinoma (cSCC), according to Mariam Totonchy, MD, an assistant clinical instructor in the Department of Dermatology at the University of Washington School of Medicine in Seattle.

Totonchy and her colleagues Chrysalyne D. Schmults, MD, FAAD, and Ashley Wysong, MD, MS, presented “Staging, Work-up and Management of High-Risk Squamous Cell Carcinoma” at the 2022 American Academy of Dermatology Annual Meeting, held from March 25 to 29 in Boston, Massachusetts.¹

Schmults is a physician at Brigham and Women’s Hospital and an associate professor of dermatology at Harvard Medical School, both in Boston, and Wysong is the founding chair and William W. Bruce, MD, distinguished chair of dermatology in the Department of Dermatology at the University of Nebraska Medical Center in Omaha.

In their critical update on managing cSCC, the presenters noted that the disease can be stratified as low risk or high risk, with the latter subtype having a propensity to be more advanced and aggressive.² Features of high-risk cSCC include a depth of invasion greater than 2 mm, poor histologic differentiation, high-risk anatomic location, perineural involvement, tumor recurrence, and patient immunosuppression.³

The presentation began with a key message that definitive standard of care when treating high- risk cSCC has not yet been established. For example, there are no guidelines on postoperative radiation therapy, indications for immunotherapy, and postoperative follow-up. Despite these uncertainties, surgical excision with Mohs micrographic surgery (MMS) does offer known advantages over standard excision, according to the presenters.

EDUCATE, ENGAGE PATIENTS ON TREATMENT CHOICES
MMS cure rates are 97% for primary tumors and 90% to 94% for recurrent tumors compared with 92% and 77%, respectively, with standard excision. Although MMS offers lower risks of metastasis and recurrence, it is not useful as a singular therapy in bone, parotid, or major intracranial nerve involvement, they said.

Cures rates for MMS decrease with tumor depth greater than 2 cm and in poorly differentiated tumors.⁴ Treatment decisions are not unilateral, and physicians should provide proper counsel so that patients can make informed decisions about their care, according to Schmults. “Having honest and kind conversations about the pros and cons of different options is key,” she said. “For example, some people are willing to lose an eye or undergo adjuvant radiation to have a higher chance of cure, while others are not. Using percentage estimates of recurrence or progression risk based on available data helps patients to compare options.”

“No 2 patients are the same and I believe communication is critical to determine the best treat- ment plan for each patient,” Totonchy added.

Other treatment modalities for high-risk cSCC include radiation therapy and immunotherapy. However, there are no clear guidelines to support radiation therapy for node-negative cSCC, and radiation therapy as a primary treatment is not recommended, given the high risk of recurrence, according to the presenters. Radiation is indicated as a primary treatment for inoperable cases in which cSCC is unresectable, incompletely resected, or involves nerves extensively.⁵

The American Society for Radiation Oncology recommends the use of postoperative radiation in the following settings: evidence of gross perineural spread, high-risk tumors, desmoplastic or infiltrative tumors, immunosuppressed patients, and positive margins untreatable with further surgery, as well as in recurrent cases. However, further studies are needed—specifically, looking at the efficacy of radiation for cSCC with nerve involvement and negative surgical margins.⁷ It has relatively few contraindications but should not be used in patients who have genetic syndromes with a predisposition to skin cancer or have connective tissue disorders, according to the guidelines.

“One important takeaway is that high-risk [cSCC] must be treated with careful work-up and planning, given the higher risk of recurrence and metastasis that is often overlooked with nonmelanoma skin cancer,” Totonchy said. “The use of radiation therapy in the management of [cSCC] is no exception to this idea.”

Another modality for high-risk cSCC is immunotherapy, which boosts the body’s nat- ural defenses to fight cancer. Currently, there are only 2 FDA-approved immunotherapies for locally advanced or metastatic cSCC not amenable to curative surgery or radiation: pembrolizumab (Keytruda; Merck & Co) and cemiplimab (Libtayo; Sanofi and Regeneron Pharmaceuticals), which are part of a class of agents known as PD-1 inhibitors. The objective response rate for cemiplimab is 47%; for pembrolizumab, 34%.

Innovations are expected soon in this rapidly growing area of cancer treatment. “Ongoing clinical trials are studying the effects of neoadjuvant immunotherapy for locally advanced cSCC that may help increase disease specific survival,” Totonchy said.

Specifically, she said, neoadjuvant immunotherapy in locoregionally advanced resectable cSCC has shown promise in a pilot phase 2 trial.⁸ This therapy could be considered in cases in which multiple, recurrent tumors were irradiated previously; a large tumor burden exists; in-transit metastasis is present; or the likelihood of clear surgical margins is low, she noted.

ADVISE PATIENTS ABOUT PREVENTION

Treatment and management are only part of the shared decision-making process for patients with cSCC. Physicians should discuss prevention and prophylaxis, according to the session’s speakers.

For cSCC prophylaxis, nicotinamide (vitamin B3) and acitretin show efficacy. In one study, results showed that nicotinamide led to a 30% reduction in new cSCCs at 12 months but lacked long-term safety.^9-11 A nationwide survey of Mohs surgeons revealed that most will prescribe the medication if a patient develops 2 or more cSCCs per year.⁹ Acitretin, a vitamin A derivative, was associated with an approximately 54% reduction in sSCCs at 2 years. For patients who do develop these high-risk cSCCs, follow-up every 3 to 6 months for 2 to 5 years is recommended, including a tumor site, nodal basin, and (if there is a history of nerve involvement) neurological examination.

The presenters recommended a full-body skin examination every 3 to 12 months because the majority of cSCCs recur within 5 years. They suggested repeat imaging every 6 to 12 months for aggressive cases or those with extensive neural involvement.⁵

Schmults remarked that the presentation high- lighted “risk stratification for those who need surveillance or additional treatment after surgery or, in extreme cases, in lieu of surgery,” a point that affects clinical practice today.

“Genomic advances, such as the 40-gene expression profile test for cSCC, will help guide some of these decisions in the coming years,” Wysong said.12 Genomic phenotyping of high-risk cSCCs also may help identify tumors at the highest risk of recurrence, metastasis, and disease-specific death, she added.

Additionally, Totonchy added, “tumor genomics will also continue to play a bigger role in man- agement over the next 3 to 5 years.”

Totonchy’s forecast: “Additional areas of research to expect in the near future relate to developing expert guidelines regarding imaging lymph node basins and randomized control trials for sentinel lymph node biopsy in high-risk SCC.”

Schmults agreed, saying, “In the next 1 to 5 years, there will be trial data emerging for neoadjuvant, adjuvant, combination, and intralesional therapies, some of which can be combined with surgery to, hopefully, augment surgical cure rates.”

The drug pipeline for these therapies is also robust.¹²

Another immune checkpoint inhibitor, nivolumab (Opdivo; Bristol Myers Squibb), is being investigated as a first line therapy in locally advanced or metastatic cSCC.¹³ An EGFR inhibitor, panitumumab (Vectibix; Amgen Inc) is also being investigated as a therapy for patients with advanced cSCC.¹⁴ There is also evidence to show that the combination of panitumumab and radiation therapy synergistically affected response.

The copresenters expressed hope that the information they offered would lead to improvements in diagnosing, staging, and treating high-risk cSCC and better patient outcomes.

Disclosures:

Schmults received grants/researching funding fees from the American Society for Dermatologic Surgery; Castle Biosciences; Genentech; InflaRx; International Society for Dermatologic Surgery; Merck; National Comprehensive Cancer Network; National Institutes of Health; Novartis Pharmaceuticals; Regeneron; and Skin Cancer Consortium.

Totonchy reported no relevant financial disclosures.
Wysong received grants/research funding from Castle Biosciences.

References:

1. Schmults CD, Totonchy M, Wysong A. Staging, work-up and management of high risk cutaneous squamous cell carcinoma. Presented at: 2022 American Academy of Dermatology Annual Meeting; March 25-29, 2022; Boston, Massachusetts.
2. Jennings L, Schmults CD. Management of high-risk cutaneous squamous cell carcinoma. J Clin Aesthet Dermatol. 2010;3(4):39-48.
3. Burton KA, Ashack KA, Khachemoune A. Cutaneous squamous cell carcinoma: A review of high-risk and metastatic disease. Am J Clin Dermatol. 2016;17(5):491-508. doi:10.1007/s40257-016-0207-3
4. Schmults CD. High-risk cutaneous squamous cell carcinoma: Identification and management. Adv Dermatol. 2005;21:133-152. doi:10.1016/j.yadr.2005.06.004
5. Que SKT, Zwald FO, Schmults CD. Cutaneous squamous cell carcinoma: incidence, risk factors, diagnosis, and staging. J Am Acad Dermatol. 2018;78(2):237-247. doi:10.1016/j.jaad.2017.08.059
6. Likhacheva A, Awan M, Barker CA, et al. Definitive and postoperative radiation therapy for basal and squamous cell cancers of the skin: Executive summary of an American Society for Radiation Oncology clinical practice guideline. Pract Radiat Oncol. 2020;10(1):8-20. doi:10.1016/j.prro.2019.10.014
7. Jambusaria-Pahlajani A, Miller CJ, Quon H, Smith N, Klein RQ, Schmults CD. Surgical monotherapy versus surgery plus adjuvant radiotherapy in high-risk cutaneous squamous cell carcinoma: a systematic review of outcomes. Dermatol Surg. 2009;35(4):574-585. doi:10.1111/j.1524-4725.2009.01095.x
8. Ferrarotto R, Amit M, Nagarajan P, et al. Pilot phase II trial of neoadjuvant immunotherapy in locoregionally advanced, resectable cutaneous squamous cell carcinoma of the head and neck. Clin Cancer Res. 2021;27(16):4557-4565. doi:10.1158/1078-0432.CCR-21-0585
9. Badri O, Schmults CD, Karia PS, Ruiz ES. Efficacy and Cost Analysis for Acitretin for Basal and Squamous Cell Carcinoma Prophylaxis in Renal Transplant Recipients. Dermatol Surg. 2021;47(1):125-126. doi:10.1097/DSS.0000000000002423
10. Chen AC, Martin AJ, Choy B, et al. A phase 3 randomized trial of nicotinamide for skin-cancer chemoprevention. N Engl J Med. 2015;373(17):1618-1626. doi:10.1056/NEJMoa150619
11. Desai S, Olbricht S, Ruiz ES, Hartman RI. Nicotinamide for keratinocyte carcinoma chemoprevention: A nationwide survey of Mohs surgeons. Dermatol Surg. 2021;47(4):452-453. doi:10.1097/DSS.0000000000002788
12. Litchman GH, Fitzgerald AL, Kurley SJ, Cook RW, Rigel DS. Impact of a prognostic 40-gene expression profiling test on clinical management decisions for high-risk cutaneous squamous cell carcinoma. Curr Med Res Opin. 2020;36(8):1295-1300. doi:10.1080/03007995.2020.1763283
13. Boutros A, Cecchi F, Tanda ET, et al. Immunotherapy for the Treatment of Cutaneous Squamous Cell Carcinoma. Front Oncol. 2021;11:733917. doi:10.3389/fonc.2021.733917
14. Munhoz RR, Camargo VPD, Marta GN, et al. CA209-9JC: A phase II study of first-line nivolumab (NIVO) in patients (pts) with locally advanced or metastatic cutaneous squamous cell carcinoma. JCO. 2020;38(15_suppl):10044-10044. doi:10.1200/JCO.2020.38.15_suppl.10044
15. Hourbeigt K, Ehret M, Visseaux L, et al. Efficacy and safety of panitumumab alone or in association with radiotherapy in unresectable cutaneous squamous cell carcinoma. J Eur Acad Dermatol Venereol. 2020;34(12):2789-2794. doi:10.1111/jdv.16465