Key Publications Non-Melanoma Skin Cancer
Non-Melanoma Skin Cancer Publications
Skin Cancer Background
General Information on Skin Cancer
- Cancer, Skin (Integument). Gruber P, Shah M, Zito PM. Stat Pearls NCBI Bookshelf. 2020.
- Differentiates nonmelanoma skin cancer (NMSC) from melano•ma
- Describes etiology, epidemiology, pathophysiology, physical exam and evaluation, and treatment.
- Incidence Estimate of Nonmelanoma Skin Cancer (Keratinocyte Carcinomas) in the US Population, 2012. Rogers HW, Weinstock MA, Feldman SR, et al. Journal of the American Medical Association (JAMA) Dermatology. 2015;151(10):1081-1086.
- Importance: Understanding skin cancer incidence is critical for planning prevention and treatment strategies and allocating medical resources. However, owing to lack of national reporting and previously nonspecific diagnosis classification, accurate measurement of the US incidence of nonmelanoma skin cancer (NMSC) has been difficult.
- Objective: To estimate the incidence of NMSC (keratinocyte carcinomas) in the US population in 2012 and the incidence of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) in the 2012 Medicare fee-for-service population.
- Design, Setting, and Participants: This study analyzes US government administrative data including the Centers for Medicare & Medicaid Services Physicians Claims databases to calculate totals of skin cancer procedures performed for Medicare beneficiaries from 2006 through 2012 and related parameters. The population-based National Ambulatory Medical Care Survey database was used to estimate NMSC-related office visits for 2012. [The study] combined these analyses to estimate totals of new skin cancer diagnoses and affected individuals in the overall US population.
- Main Outcomes and Measures: Incidence of NMSC in the US population in 2012 and BCC and SCC in the 2012 Medicare fee-for-service population.
- Results: The total number of procedures for skin cancer in the Medicare fee-for-service population increased by 13% from 2,048,517 in 2006 to 2,321,058 in 2012. The age-adjusted skin cancer procedure rate per 100,000 beneficiaries increased from 6075 in 2006 to 7320 in 2012. The number of procedures in Medicare beneficiaries specific for NMSC increased by 14% from 1,918,340 in 2006 to 2,191,100 in 2012. The number of persons with at least 1 procedure for NMSC increased by 14% (from 1,177,618 to 1,336,800) from 2006 through 2012. In the 2012 Medicare fee-for-service population, the age-adjusted procedure rate for BCC and SCC were 3280 and 3278 per 100,000 beneficiaries, respectively. The ratio of BCC to SCC treated in Medicare beneficiaries was 1.0. [The study estimates] the total number of NMSCs in the US population in 2012 at 5,434,193 and the total number of persons in the United States treated for NMSC at 3,315,554.
- Conclusions and Relevance: This study is a thorough nationwide estimate of the incidence of NMSC and provides evidence of continued increases in numbers of skin cancer diagnoses and affected patients in the United States. This study also demonstrates equal incidence rates for BCC and SCC in the Medicare population.
Squamous Cell Carcinoma
- Cancer, Squamous Cell of the Skin. Howell JY, Ramsey ML. Stat Pearls NCBI Bookshelf. 2020.
- Squamouscell carcinoma of the skin or cutaneous squamous cell carcinoma is the second most common form of skin cancer in the United States, behind basal cell carcinoma. Squamous cell carcinoma has precursor lesions called actinic keratosis, exhibits tumor progression and has the potential to metastasize in the body. Ultraviolet (UV) solar radiation is the primary risk factor in the development of cutaneous squamouscellcarcinoma and the cumulative exposure received over a lifetime plays a major part in the development of this cancer.
- Surgical excision is the primary treatment modality for cutaneous squamouscell carcinoma, with Mohs micrographic surgery being the preferred excisional technique for squamous cell carcinoma of the head and neck, and in other areas of high risk or squamous cell carcinoma with high-risk characteristics. Radiation therapy is reserved for squamous cell carcinoma in older patients or those who will not tolerate surgery, or when it has not been possible to obtain clear margins surgically. Adjuvant radiotherapy is commonly after surgical treatment in very high tumors. Immunosuppression significantly increases the risk of squamous cell carcinoma over the course of an individual’s life.
- Metastasis is uncommon for squamouscell carcinomas arising in areas of chronic sun exposure, but it can take place, and the risk is increased in immunosuppressed patients. Patients with cutaneous squamous cell carcinoma should be examined regularly and remember to use measures to protect from UV damage
- Squamous Cell Skin Cancer Quick Guide. National Comprehensive Cancer Network (NCCN) 2019.
- Summary of key points from the NCCN Patient Guidelines on Squamous Cell Carcinoma including information on disease process, risk factors, treatment options, and prevention.
- Squamous Cell Skin Cancer Guidelines. NCCN 2019.
- Extensive patient-focused information on squamous cell carcinoma including information on pathophysiology, risk factors, prevention, prognosis and recommendations on treatment.
Basal Cell Carcinoma
- Basal Cell Carcinoma. McDaniel B, Badri T. Stat Pearls NCBI Bookshelf. 2020.
- Basal cell carcinoma (BCC), previously known as basal cell epithelioma, is the most common cancer in Humans. BCC mostly arises on sun-damaged skin and rarely develops on the mucous membranes or palms and soles. Basal cell carcinoma is usually a slow-growing tumor for which metastases are rare. Although rarely fatal, BCC can be highly destructive and disfigure local tissues when treatment is inadequate or delayed.
- On clinical examination, BCC usually appears as flesh- or pink-colored, pearly papules with overlying ulceration or telangiectatic vessels. BCC occurs on the head or neck in the majority of cases. More than 26 different subtypes of BCC are described in the literature, but most dermatologists agree on four major, distinctive, clinicopathologic types: (1) nodular, (2) superficial, (3) morpheaform, and (4) fibroepithelial (also known as fibroepithelioma of Pinkus). Combinations of these four types with nodular BCC can occur as well. The majority of BCCs are amelanotic, but variable amounts of melanin may be present within these tumors.
- The current mainstay of BCC treatment involves surgical modalities such as excision, electrodesiccation and curettage (EDC), cryosurgery, and Mohs micrographic surgery. Such methods are typically reserved for localized BCC and offer high 5-year cure rates, generally over 95%
- Basal Cell Carcinoma Overview. Skin Cancer Foundation 2019.
- Key points from the Skin Cancer Foundation on basal cell carcinoma including risk factors, warning signs, and treatment options.
Current Management of Non-Melanoma Skin Cancer
Non-Melanoma Skin Cancer
- Immunotherapy to Treat Cancer. National Cancer Institute 2020.
- As part of its normal function, the immune system detects and destroys abnormal cells and most likely prevents or curbs the growth of many cancers.
- People whose tumors contain tumor-infiltrating lymphocytes (TILs) often do better than people whose tumors don’t contain them.
- Immunotherapy is a type of cancer treatment that helps your immune system fight cancer.
- Management of keratinocyte carcinoma – special considerations in the elderly. Bailey A, Vasicek B, Tao J, et al. International Journal of Women’s Dermatology. 2019; 5(4): 235–245.
- Keratinocyte carcinomas (KCs) are now an epidemic in The United States of America, especially in elderly patients.
- KCs, including basal cell carcinoma and squamous cell carcinoma, can lead to disfigurement and occasionally death. However, the lower mortality rate associated with KC compared with melanoma allows for increased flexibility in the selection of treatment.
- Flexibility in treatment is particularly important in the elderly given that this patient population often has medical comorbidities that should be considered. These patients may have multiple KCs, higher risk tolerance to recurrence, and different concerns about cosmetic outcomes compared with their younger counterparts.
- [The authors reviewed] treatment options for KCs and how the selection of each option may affect the elderly patient.
- Imiquimod for the Treatment of Basal Cell or Squamous Cell Carcinoma: A Review of Clinical Effectiveness and Cost-Effectiveness. Banerjee S, Kunelis D. Canadian Agency for Drugs and Technologies in Health.
- The purpose of this review is to compare the clinical effectiveness and cost-effectiveness of IMQ [imiquimod] to other treatment modalities for the treatment of BCC or SCC.
Squamous Cell Carcinoma
- Squamous Cell Carcinoma: An update on diagnosis and treatment. Combalia A, Carrera C. Dermatology Practical & Conceptual. 2020; 10(3): e2020066.
- Squamous cell carcinoma (SCC) accounts for most nonmelanoma skin cancer–related metastatic disease and deaths.
- Histopathology and correct surgical excision remain the gold standard for the diagnosis and treatment of SCC; however, new diagnostic imaging techniques such as dermoscopy and reflectance confocal microscopy have increased the diagnostic accuracy in terms of early recognition, better differential diagnosis, more precise selection of areas to biopsy, and noninvasive monitoring of treatments.
- The therapeutic intervention in patients with severe actinic damage and multiple in situ/low-risk SCC, and the development of innovative treatments such as epidermal growth factor receptor inhibitors and immune checkpoint inhibitors for locally advanced and metastatic SCC, are improving considerably the approach to the disease. This review summarizes the up-to-date knowledge in the field of detection, treatment, and monitoring of cutaneous SCC.
- Squamous Cell Carcinoma Treatment Option Overview. Skin Cancer Foundation 2019.
- Description of treatment options and when treatment may be used from the Skin Cancer Foundation for the treatment of early-stage squamous cell carcinoma
- Squamous Cell Patient Guidelines. NCCN 2019.
- Provides overview of treatment options for squamous cell carcinoma stratified by regional SCC.
- Immunotherapy for Advanced Squamous Cell Carcinoma. American Cancer Society 2020.
- Immunotherapy is the use of medicines to stimulate a person’s own immune system to recognize and destroy cancer cells more effectively
- Provides overview of immunotherapy, checkpoint inhibitors, for advanced squamous cell carcinoma.
Basal Cell Carcinoma
- Basal Cell Carcinoma Treatment Option Overview. Skin Cancer Foundation 2019.
- Description of treatment options and when treatment may be used from the Skin Cancer Foundation for the treatment of basal cell carcinoma.
- Surgery Versus Imiquimod for Nodular and Superficial Basal Cell Carcinoma: 5-Year Results of the SINS Randomized Controlled Trial. Williams HC, Bath-Hextall F, Ozolins M, et al. Journal of Investigative Dermatology. 2017; 137:614-619.
- [The investigators] previously reported modest clinical 3-year benefit for topical imiquimod compared with surgery for superficial or nodular basal cell carcinoma at low-risk sites in our noninferiority randomized controlled SINS trial. Here [the study reports] 5-year data.
- Participants were randomized to imiquimod 5% cream once daily (superficial basal cell carcinoma, 6 weeks; nodular basal cell carcinoma, 12 weeks) or excisional surgery (4-mm margin). The primary outcome was clinical absence of initial failure or signs of recurrence at the 3-year dermatology review. Five-year success was defined as 3-year success plus absence of recurrences identified through hospital, histopathology, and general practitioner records.
- Of 501 participants randomized, 401 contributed to the modified intention-to-treat analyses at year 3 (primary outcome), 383 (96%) of whom had data at year 5. Five-year success rates for imiquimod were 82.5% (170/206) compared with 97.7% (173/177) for surgery (relative risk of imiquimod success = 0.84, 95% confidence interval = 0.77–0.91, P< 0.001). These were comparable to year 3 success rates of 83.6% (178/213) and 98.4% (185/188) for imiquimod and surgery, respectively. Most imiquimod treatment failures occurred in year 1.
- Although surgery is clearly superior to imiquimod, this study shows sustained benefit for lesions that respond early to topical imiquimod.
- Surgical excision versus imiquimod 5% cream for nodular and superficial basal-cell carcinoma (SINS): a multicenter, non-inferiority, randomized controlled trial. Bath-Hextall F, Ozolins M, Armstrong SJ, et al. Lancet Oncol. 2014;15(1):96-105.
- Background: Basal-cell carcinoma is the most common form of skin cancer and its incidence is increasing worldwide. [the study] aimed to assess the effectiveness of imiquimod cream versus surgical excision in patients with low-risk basal-cell carcinoma.
- Methods: [the study] did a multicentre, parallel-group, pragmatic, non-inferiority, randomised controlled trial at 12 centres in the UK, in which patients were recruited between June 19, 2003, and Feb 22, 2007, with 3 year follow-up from June 26, 2006, to May 26, 2010. Participants of any age were eligible if they had histologically confirmed primary nodular or superficial basal-cell carcinoma at low-risk sites. [The study] excluded patients with morphoeic or recurrent basal-cell carcinoma and those with Gorlin syndrome. Participants were randomly assigned (1:1) via computer-generated blocked randomisation, stratified by centre and tumour type, to receive either imiquimod 5% cream once daily for 6 weeks (superficial) or 12 weeks (nodular), or surgical excision with a 4 mm margin. The randomisation sequence was concealed from study investigators. Because of the nature of the interventions, masking of participants was not possible and masking of outcome assessors was only partly possible. The trial statistician was masked to allocation until all analyses had been done. The primary outcome was the proportion of participants with clinical success, defined as absence of initial treatment failure or signs of recurrence at 3 years from start of treatment. [the study] used a prespecified non-inferiority margin of a relative risk (RR) of 0.87. Analysis was by a modified intention-to-treat population and per protocol. This study is registered as an International Standard Randomised Controlled Trial (ISRCTN48755084), and with ClinicalTrials.gov, number NCT00066872.
- Findings: 501 participants were randomly assigned to the imiquimod group (n=254) or the surgical excision group (n=247). At year 3, 401 (80%) patients were included in the modified intention-to-treat group. At 3 years, 178 (84%) of 213 participants in the imiquimod group were treated successfully compared with 185 (98%) of 188 participants in the surgery group (RR 0.84, 98% CI 0.78-0.91; p<0.0001). No clear difference was noted between groups in patient-assessed cosmetic outcomes. The most common adverse events were itching (211 patients in the imiquimod group vs 129 in the surgery group) and weeping (160 vs 81). [the study] recorded serious adverse events in 99 (40%) of 249 participants in the imiquimod group and 97 (42%) of 229 in the surgery group had serious adverse events, but none were regarded as related to treatment. 12 (5%) participants in the imiquimod group withdrew because of adverse events compared with four (2%) in the surgery group.
- Interpretation: Imiquimod was inferior to surgery according to our predefined non-inferiority criterion. Although excisional surgery remains the best treatment for low-risk basal-cell carcinoma, imiquimod cream might still be a useful treatment option for small low-risk superficial or nodular basal-cell carcinoma dependent on factors such as patient preference, size and site of the lesion, and whether the patient has more than one lesion.
LTX-315 Mechanism of Action
- Lactoferrin-derived lytic peptide LTX-315. NCI Drug Dictionary 2020.
- A peptide derived from human lactoferrin, with potential lytic and immunostimulating activities.
- LTX-315 may bind to the tumor cell membranes and subsequently lyse tumor cells, thereby inducing tumor cell necrosis. In turn, presentation of the tumor antigens to the immune system may induce systemic innate and adaptive immune responses mediated by anti-tumor natural killer (NK) cells, cytotoxic T lymphocytes, and natural killer T (NKT) cells. This may trigger an immune response against tumor associated antigens on tumors distant from the primary tumor.
- LTX-315: A first-in-class oncolytic peptide that reshapes the tumor microenvironment. Lytix Biopharma 2017.
- LTX-315 induces a unique type of immunogenic cell death
- LTX-315 treatment leads to increased tumor infiltration of CD8+ T cells
- LTX-315 demonstrates synergy with other standard of care cancer therapies
- LTX-315 increases the number and diversity of T cell clones
- LTX-315, CAPtivating Immunity with Necrosis. Sistigu A, Manic G, Vitale I. Cell Cycle. 2016; 15(9): 1176–1177.
- LTX-315 is a helical CAP [Cationinc Antimicrobial Peptide] optimized for membrane destabilization, which has been recently shown to induce cell lysis when administered intralesionally
- This [leads] to the release of immunomediators into the tumor microenvironment and unleashed an inflammatory response whereby specific cytotoxic T cells eradicated residual cancer cells.
- LTX-315 epitomizes an oncolytic agent that, due to its immunogenic potential, may represent a new cancer immunotherapeutic approach for triggering tumoricidal immune responses at will
LTX-315 Basic/Background Research
LTX-315 sequentially promotes lymphocyte-independent and lymphocyte-dependent antitumor effects. Liao HW, Garris C, Pfirschke C, et al. Cell Stress. 2019; 3(11): 348–360.
- LTX-315 is an oncolytic peptide that has antitumor efficacy in mice grafted with various tumor cell lines and is currently being tested in Phase II clinical trials.
- Here [the study] aimed to further evaluate LTX-315 in conditional genetic mouse models of cancer that typically resist current treatment options and to better understand the drug’s mode of action in vivo. [The study reports] LTX-315 mediates profound antitumor effects against Braf-and Pten-driven melanoma and delays the progression of Kras- and P53-driven soft tissue sarcoma in mice.
- Additionally, [the study shows] in melanoma that LTX-315 triggers two sequential phases of antitumor response. The first phase of response, which begins within minutes of drug delivery into tumors, is defined by disrupted tumor vasculature and decreased tumor burden and occurs independently of lymphocytes. The second phase of response, which continues over weeks, is defined by long-term alteration of the tumor microenvironment; the changes induced by LTX-315 are most notably characterized by CD8+ T cell infiltration. [The study further shows] that these CD8+ T cells are involved in suppressing melanoma outgrowth in mice and report similar CD8+ T cell infiltration following LTX-315 treatment in melanoma and sarcoma patients.
- Taken together, these findings reveal LTX-315’s multiple antitumor effects, including disrupting the tumor vasculature and promoting the conversion of poorly immunogenic tumors into ones that display antitumor T cell immunity.
- Cell cycle progression data on human skin cancer cells with anticancer synthetic peptide LTX-315 treatment. Santa-Gonzalez GA, Patino-Gonzalez E, Manrique-Moreno M. Data in Brief. 2020; 20: 105443.
- Skin cancer, including melanoma and non-melanoma (NMSC), represents the most common type of malignancy in the white population. The incidence rate of melanoma is increasing worldwide, while the associated mortality remains stable. On the other hand, the incidence of NMSC varies widely.
- Camilio and collaborators recently described the anticancer properties of LTX-315, a novel synthetic anticancer peptide, commercialized as Oncopore™. Despite various studies demonstrating the efficiency of LTX-315 therapy in inducing cancer cell death, the effects on cell cycle progression of this antitumoral peptide are poorly understood.
- In this research, [the study presents] data about the effect of LTX-315 on the cell cycle of two skin cancer cell lines: epidermoid carcinoma cells (A431) and melanoma cells (A375); as well as on an immortalized normal keratinocyte cell line, HaCaT. Additionally, its cytotoxicity on the cells was determined by measuring the uptake of propidium iodide, in order to establish its relationship with cell cycle progression. The analysed data obtained by flow cytometry show different cell cycle distributions in non-tumoral and skin cancer-derived cell lines in response to LTX-315 treatment. Non-tumoral cells showed a sub-G1 peak, while for tumoral cells there was a shift in the G1peak without producing an obvious distant and distinct sub-G1 peak. This data is in accordance with a major decrease in cell viability in non-cancer cells.
LTX-315 Clinical Data
- LTX-315 Clinical Trials. Clinicaltrials.gov 2020.
- List of Ongoing and Completed Clinical Trials Registered with ClinicalTrials.gov.
*LTX-315 has not been approved by the FDA
VP-315, a Non-surgical Immunotherapy in Subjects with Biopsy Proven Basal Cell Carcinoma
- Proof of Concept Study to to assess safety, tolerability, and maximum tolerated dose (MTD) of ascending dose strengths of VP-315 in adult subjects with biopsy proven BCC. Finding published at the Congress of Clinical Dermatology. View Poster.
- VP-315: An Investigational Non-surgical Immunotherapy in Subjects with Biopsy Proven Basal Cell Carcinoma presentation given at the American Academy of Dermatology (AAD) 2023 Innovation Academy Meeting. View Presentation.
* VP-315 is being developed for BCC