Background

Non-melanoma skin cancer (NMSC) is the most common cancer diagnosed in the United States and it is comprised mostly of basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and squamous cell carcinoma in-situ (SCCIS) [1]. In 2012, NMSC incidence was estimated at 5·43 million NMSC lesions in 3·32 million individuals in the U.S [2]. It is estimated that the overall incidence of BCC increased by 145% between 1976–1984 and 2000–2010, and the overall incidence of SCC increased 263% over that same period [3].

Despite NMSC having a low mortality, high cure rates, rare metastasis, and only accounting for 0·1% of cancer deaths, the standard of treatment is surgical removal [1]. Surgical options consist of Mohs micrographic surgery (MMS), excision, shave removal, curettage, and electrodessication [4]. However, numerous nonsurgical, non-invasive modalities exist including topical treatments (i.e., imiquimod, 5-flurouracil [5-FU] etc.), cryotherapy, photodynamic therapy (PDT), laser therapy, and radiotherapy with several techniques available within each category. However, surgery, specifically MMS, has remained the mainstay of treatment as the literature promises the highest cure-rates at around 99% [5, 6].

Multiple radiation modalities exist for the treatment of NMSC, including brachytherapy, electron beam radiotherapy (EBRT), external radiation therapy (XRT), and superficial radiation therapy (SRT). Specifically, superficial radiation therapy, has been used by dermatologists for the past century to treat NMSC [7]. With the advent of MMS, this modality fell out of favor. However, more recently there has been advancements to SRT, including the use of a high frequency 22 megahertz (MHz) dermal ultrasound (US) to visualize superficial depth of the skin. This has led to the development of high-resolution dermal ultrasound image guided superficial radiotherapy, designated here as (US-SRT) and commercially known as image-guided SRT (IGSRT). Commercial units became available in 2014 that allowed for lesion visualization prior to, during, and after treatment. A recently published study by Yu et al. using US-SRT (“IGSRT”) to treat 2917 early-stage keratinocytic cancers yielded a high local control (LC) rate of 99·3% [8]. An updated abstract that added 93 patients and 133 lesions for a total of 1725 patients with 3050 early-stage keratinocytic lesions showed a continued high local control (LC) of 99·2% [9]. This suggests that US-SRT can offer comparable cure rates to that of the current “gold standard” treatment modality, namely MMS, for early-stage NMSC without needing surgery and its associated risks, discomfort, and cosmetic sequalae.Footnote 1

Objective

To statistically evaluate the local control (LC) differences, if any, of US-SRT versus non-image-guided radiotherapy modalities for the treatment of early-stage epithelial cancer.

Methods

Source information

US-SRT results have been investigated in two seminal studies referenced hereafter as the 2021 US-SRT study and the 2022 US-SRT study [8, 9]. Data from the 2021 US-SRT study was obtained via direct chart analysis of patients with histopathologic confirmed NMSC treated with US-SRT from multiple institutions. Data from the 2022 US-SRT study utilized the same data from the 2021 US-SRT study with the addition of 133 histopathological confirmed NMSC from 94 patients with updated follow-up intervals. Data on the additional 133 histopathologic confirmed NMSC in 94 patients was previously published [10].

US-SRT outcomes included in the present analyses are from a subset of the 2021 US-SRT study patients who have a follow-up of greater than 52 weeks; and are from the entire study population of the 2022 US-SRT study.

The American Society of Radiation Oncology (ASTRO) published a literature review containing 143 studies on curative radiation treatment for NMSC [11]. A subset of modern, pertinent, comparable studies that utilized superficial radiotherapy (SRT) and external radiotherapy (XRT) without image-guidance were identified as meeting the following inclusion/exclusion criteria.

Inclusion

Only studies performed in the USA.

Exclusion

Meta-analysis, brachytherapy, pre-operative, post-operative ± chemo/targeted agents used, recurrent or predominately recurrent, prior radiotherapy, T4 only/predominant, metastatic to parotids, involvement of parotids, wound healing only, no local control reported, perineural invasion in \(\ge\) 50% of cases, and those lesions arising from scar.

These criteria resulted in four high-quality, recent, evidenced-based studies, each with greater than 100 subjects. The four studies provided the XRT/SRT outcome data for this study and are hereafter referenced as the Lovett study, Locke study, Silverman study, and Cognetta study [12,13,14,15].

Local Control (LC) calculation

Local Control for this analysis was defined as complete resolution of the treated lesion without evidence of recurrence. Lesion counts for the two US-SRT studies and the four XRT/SRT studies were used to compute LC as “Number of lesions that did not recur / Total number of lesions”. Lesions were analyzed as independent events. Only Tis, T1 and T2 lesions were included. Specifically, the 2 US-SRT studies only had Tis, T1 and T2 lesions in the entire cohort whereas in the other studies, only early stage lesions of stage 0 to stage II( Tis, T1 and T2) were included for analysis. This was done to allow proper comparisons (of “apples to apples”) so that better local control caused by higher proportion of favorable patients as a confounding factor is eliminated.

Statistical analysis

Data availability in the two US-SRT studies and the four XRT/SRT studies made it possible to compare each US-SRT study (i.e., Yu study and Moloney study) to the following XRT/SRT studies: Lovett, Locke, Silverman, and Cognetta for BCC; Lovett, Locke, and Cognetta for SCC; and Cognetta for SCCIS. For each comparison, a logistic model was implemented that contained the effect of treatment with treatment levels defined as the studies under consideration. Odds ratios were then derived that compared the US-SRT studies to each available XRT/SRT study and to all XRT/SRT studies combined.

Role of the funding source

The sponsor of the study (SkinCure Oncology) was not involved in the study design, collection, analysis, interpretation of data, or writing of the report. The decision to submit the paper for publication was solely that of Dr. Lio Yu and the co-authors.

Results

Table 1 compares each of the US-SRT studies to each XRT/SRT study (Lovett, Locke, Silverman, and Cognetta).Footnote 2 Comparisons using odds ratios from logistic regression models were made for BCC, SCC, and SCCIS, individually, with odds ratios greater than unity (1) favoring US-SRT. As indicated in Table 1, not all studies evaluated all histologic tumor categories (SCC, SCCIS, BCC), and therefore, only studies that included a given histologic tumor category could be used as a comparator study in the evaluation of that same histologic tumor category. Table 1 also reports comparisons by tumor category between each US-SRT study and all comparator XRT/SRT studies combined. Finally, the LC odds can be converted to a probability with an asymmetrical 95% confidence interval. For the 2021 and 2022 US-SRT studies, separately, LC probabilities and 95% confidence intervals were calculated for each US-SRT study. This allows an odds ratio comparison to be envisioned as a plotted difference in LC probabilities.

Table 1 Recurrence and Local Control Events for Basal Cell Carcinoma (BCC), Squamous Cell Carcinoma (SCC) and Squamous Cell Carcinoma In Situ (SCCIS) with High resolution dermal ultrasound image guided superficial radiotherapy (US-SRT) versus External Radiation Therapy (XRT) / Superficial Radiation Therapy (SRT) Contrasts Using Odds Ratios (OR)
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Table 1 indicates that US-SRT LC was statistically superior to the comparator XRT/SRT studies individually, collectively, and stratified by histologic tumor type, with p-values ranging from p < 0·0001 to p = 0·0438. Figure 1 plots the LC probabilities for each US-SRT study compared to each XRT/SRT study separated by histology. Figure 1 affirms graphically the findings shown in Table 1.

Fig. 1
figure 1

Basal Cell Carcinoma (BCC), Squamous Cell Carcinoma (SCC) and Squamous Cell Carcinoma In Situ (SCCIS) Probabilities of Local Control for the High resolution dermal ultrasound image guided superficial radiotherapy (US-SRT) and External Radiation Therapy (XRT) / Superficial Radiation Therapy (SRT) Investigations

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Discussion

Our analysis shows US-SRT confers a statistically significant improvement in local control for all histologic subtypes of epithelial NMSC (BCC, SCC, SCCIS) compared to all four high-quality, recent, large studies using non-image-guided forms of radiotherapy (XRT/SRT). The improvement in local control can be attributed to the image-guided component of superficial radiotherapy, as the high definition integrated dermal ultrasound with doppler features allows for visualization of the early-stage lesions’ depth, breadth, and overall configuration prior to, during, and after treatment. Visualization during treatment allows for the treatment provider to adjust radiotherapy dosages and energies of penetration daily if necessary. Visualization after treatment allows for confirmation of lesion resolution/response.

Advantages of US-SRT include high cure-rates as demonstrated in the 2021 and 2022 papers. It is cost effective, due to its low-recurrence rate. It offers cosmetic benefits as it is tissue sparing and the majority of NMSC lesions occur in cosmetically sensitive areas, such as the head and neck. Patients can avoid pain, scarring and risk of infection and/or bleeding since this is a non-surgical treatment modality. As many patients often have more than one lesion diagnosed simultaneously, multiple lesions can also be treated synchronously with US-SRT. Offices that use US-SRT have reported overall excellent (> 95%) patient satisfaction and provider satisfaction (internal data). Indeed, a wide variety of patients could benefit from US-SRT, especially those with lesions on the head and neck region such as the ear, nose, or eyelids for functional preservation purposes, on the face where cosmesis is of concern, as well as the scalp where surgical closure is challenging often requiring flap placement for larger or multiple adjacent/confluent lesions. In the below knee locations where poor vascularization can result in protracted non-healing, US-SRT has an advantage over surgery because of its non-invasive nature.

Absolute and relative contraindications to US-SRT, as previously described in the 2021 US-SRT studies, include lesion invasion to underlying bone or muscle, thickness > 6 mm, previous radiation to the same lesion site, ataxia telangiectasia, active connective tissue disease, active lupus or rheumatologic disease, concomitant management with radiation sensitizing chemotherapy agent, T4 stage, and node positive status [8].

US-SRT could be considered the preferred standard non-surgical radiotherapeutic treatment modality for appropriate patients with early-stage epithelial skin cancers (BCC, SCC, SCCIS) with comparable LC to MMS without the drawbacks of surgery. At the minimum, patients should be presented with the option to have their NMSC treated with US-SRT.

Limitations

No randomized controlled trial exists for direct comparison of US-SRT to radiotherapy modalities, including superficial and external radiotherapy. The follow-up periods in this paper, though long enough to reasonably assure meaningful and accurate US-SRT to XRT/SRT comparisons, are unequal among studies.Footnote 3

Conclusion

Image guidance with high resolution dermal ultrasound in the form of US-SRT is shown to confer a statistically significant advantage in lesion local control over non- image guided forms of SRT or XRT in all subtypes of cutaneous epithelial NMSC and should be considered the preferred standard of non-surgical treatment for early stage cutaneous BCC, SCC, and SCCIS.