Top 10 research priorities for cutaneous squamous cell carcinoma: results of the Skin Investigation Network of Canada Priority Setting Initiative

Abstract

The Skin Investigation Network of Canada (SkIN Canada) completed a national priority-setting initiative to identify the top 10 knowledge uncertainties for SCC based on the James Lind Alliance principles. Overall, 64 patients, clinicians and researchers provided input in two survey rounds and one workshop. The top 10 list of research priorities will help the skin research community, funders and policymakers to address key knowledge uncertainties for the benefit of patients with SCC.

Dear Editor, Cutaneous squamous cell carcinoma (cSCC) is the second most common human malignancy in White populations. Although incidence data are limited in North America owing to the exclusion of keratinocyte carcinoma from most cancer registries, data from the UK and regions of Germany, Canada and the USA show that the incidence of cSCC is continuing to increase.^1–3 Population-based mortality due to keratinocyte carcinoma has also increased in Canada in recent decades.² Ultraviolet exposure is the major carcinogen for most cSCC. Other risk factors include human papillomavirus infection, occupational and arsenic exposures, various genodermatoses, scarring inflammatory dermatoses, chronic wounds and burns.

Potentially curative local treatment options for cSCC include surgery, radiation therapy and topical immunotherapy/chemotherapy, which can cause significant morbidity and affect quality of life. A subset of patients has locally advanced or metastatic cSCC (advanced cSCC) that is challenging to treat. Recently approved immunotherapies for advanced cSCC include checkpoint inhibitors, providing an overall response rate of approximately 50% when used as a first-line therapy.⁴ However, immunotherapy is contraindicated in the high-risk population of solid-organ transplant recipients, who have a 5% risk of advanced cSCC.⁵

In order to identify the most important research priorities for cSCC, the Skin Investigation Network of Canada (SkIN Canada) established a priority setting initiative (PSI) designed and conducted according to the James Lind Alliance’s Guiding Principles of Priority Setting Exercises.⁶ Stakeholders in the PSI were primarily patients, caregivers and healthcare professionals, ensuring that the perspectives of those living with and caring for cSCC were incorporated. Skin researchers were also given the opportunity to suggest knowledge gaps, but they were not involved in ranking them.

SkIN Canada used a multistep process that has been detailed previously.⁷ Patients, caregivers, clinicians and researchers provided input on cSCC across two survey rounds and a final workshop. The first survey asked individuals from all stakeholder categories to submit research questions. Eighty-six submissions were received from 38 respondents (8 patients/caregivers, 21 dermatologists, 1 plastic surgeon, 4 nurses, 4 researchers). Duplicates were removed to produce 46 unique research questions.

The second survey (40 respondents: 6 patients, 31 dermatologists, 1 plastic surgeon, 1 medical oncologist, 1 nurse) asked patients, caregivers and healthcare providers to rank their top 10 priorities among the list of 46 unique research questions. An aggregated list of the top 20 research questions (10 from patients/caregivers and 10 from clinicians) was subsequently discussed by 15 participants (6 patients, 6 Mohs surgeons, 2 dermatologists, 1 medical oncologist) during the final workshop. After structured discussion facilitated by a James Lind Alliance advisor, each participant submitted their final ranked votes. The top 10 priorities for cSCC are listed in Table 1.

Table 1.

Top 10 research priorities for cutaneous squamous cell carcinoma (cSCC), ranked in order of priority

Rank	Research priority
1	To what extent does adjuvant radiation therapy after surgery help prevent recurrence or metastasis of cSCC?
2	What genetic/molecular mechanisms drive cSCC development and lead some tumours to metastasize?
3	When should diagnostic imaging (e.g. computed tomography and ultrasound) be done to look for cSCC metastasis and which are the most effective methods?
4	What is the role of sentinel lymph node biopsy or ultrasound monitoring of lymph nodes for cSCC?
5	What is the best way to identify perineural tumour spread before surgery?
6	How effective and safe are chemopreventive agents (e.g. retinoids, nicotinamide and capecitabine) in the long-term prevention of cSCC in immunosuppressed patients who have received an organ transplant?
7	Which surgical and nonsurgical (radiation, systemic therapy) treatments are more effective (compared with each other) in treating low-risk, high-risk and metastatic cSCC?
8	What staging system and risk factors are most useful to predict whether a cSCC will be aggressive?
9	What is the role of the immune system in the development of cSCC?
10	What is the role of chemoprevention in nonimmunosuppressed patients?

Recurring themes were identified from discussions during the workshop. Participants felt that the communication of information to patients experiencing cSCC can be improved. People with lived experience with cSCC emphasized the importance of having comprehensive, easy-to-understand take-away information from the appointment when they first learn about their cancer diagnosis. As one participant said: ‘Once you hear that word [cancer], you “stop listening”.’ Many participants highlighted the role of the immune system in the pathogenesis of cSCC and its associated aggressiveness, whether patients are immunocompetent or immunosuppressed. Diagnostic modalities and patient stratification from the initial diagnosis were often mentioned, with particular interest in identifying features of high-risk disease (global prognostication, identification of perineural involvement, lymph node evaluation). Imaging to detect metastasis for high-risk cSCC is used inconsistently between practice settings, and participants suggested a need for better evidence-based guidance to inform prognosis, monitoring and treatment. Participants also noted that clear guidelines and data comparing different classes of treatment modalities are key in managing patients according to disease stage (low-risk, high-risk, locally advanced, metastatic). Finally, the theme of chemoprevention was deemed essential in organ transplant recipients given their propensity to develop high-risk cSCC and advanced cSCC.

A recent priority setting initiative in the UK identified the top 10 evidence uncertainties for surgical management of skin cancer.⁸ Similarly to our initiative, the role of sentinel lymph node biopsy in skin cancers, including cSCC, was highly ranked. None of their other nine priorities overlapped with those identified in our top 10 list, as the SkIN Canada initiative had a broader scope.

The top 10 research priorities we identified for cSCC encompass some of the most important issues faced by the skin cancer community and will guide the development of a clinical and translational research agenda by SkIN Canada and other stakeholders. Addressing these questions will help ensure that future research is focused on the unmet needs of patients with cSCC, to improve clinical outcomes.

Funding sources

conducted by the Skin Investigation Network of Canada (SkIN Canada), funded by the Canadian Institutes of Health Research (CIHR).

Data availability

the data underlying this article will be shared upon reasonable request to the corresponding author.

Ethics statement

the SkIN Canada Priority Setting Initiative has been reviewed and approved by Women’s College Hospital Institutional Research Ethics Review Board.

Supporting Information

Additional Supporting Information may be found in the online version of this article at the publisher’s website.

Appendix S1 Complete list of author affiliations.

Appendix S2 Complete list of members of the Skin Investigation Network of Canada Priority Setting Collaborative.