A meta-analysis by Yu et al. compared NMSC local control (LC)/cure rates from studies describing three different radiation modalities: external beam radiotherapy (XRT), SRT without HRDUS, and IGSRT. The study found that IGSRT overall local control rates (99.3% [9] and 99.2% [16]) were statistically superior to those of XRT or SRT without HRDUS in all subtypes individually or collectively (LC 91–96.9% for BCC, 81.1–97% for SCC, 97.8% for SCC-IS). These results can be attributed to the use of US visualization before, during, and after treatment of NMSC lesions, allowing providers to determine tumor breadth and depth to select field size, energy, and dose prior to treatment, make adjustments to therapy as needed in real time, and confirm treatment response post therapy. This technology provides patients a viable option for the non-surgical treatment of NMSC lesions [17]. These findings were verified by a log regression analysis performed by Yu et al. in 2023, which showed that compared to four studies utilizing non-image guided radiotherapy (LC 90.1–96.8% for BCC, 76.7–96.9% for SCC, 97.7% for SCC-IS), LC/cure rates for all subtypes of epithelial NMSC had a statistically significant improvement through use of IGSRT (LC 98.9–99.1% for BCC, 99.2–99.3% for SCC, 99.5–99.8% for SCC-IS) [18]. As a result of the high-definition ultrasound with Doppler that allows for visualization of the lesions’ overall configuration before, during, and after treatment, this statistically significant improvement was attributed to the HRDUS aspect of superficial radiotherapy. This allows the treatment provider to adjust dose and energy up to as often as daily, if needed, and confirm lesion response to treatment [18].

Table 2 provides a summary of the following IGSRT literature review. In 2021 Yu et al. described the treatment of 1,632 patients with 2,917 NMSC tumors using IGSRT. Tumor types were as follows: Basal cell carcinoma (BCC): 48.2%, squamous cell carcinoma (SCC): 31.5% and squamous cell carcinoma in situ (SCC-IS): 20.7%. Mean follow-up was 69.8 weeks or 1.34 years and the cure rate was 99.3%. Through the use of IGSRT, the depth of the tumor can be determined and correlated with the percentage depth dose (PDD) tables. This allows optimal energy selection (50, 70 or 100 kV) before and during the treatment course. As significant changes in tumor depth can be detected from one fraction to another, IGSRT allows adjustments to be made as needed. In this study, 29% of NMSC lesions were treated with multiple energies. The use of HRDUS for daily evaluation of tumor depth improves the delivery of optimal radiation energy and dose throughout the fractionated treatment scheme, as evidence by the high cure rate. To evaluate treatment related adverse events, the Radiation Therapy Oncology Group (RTOG) Acute Radiation Morbidity Scoring Criteria (Table S1 in the electronic supplementary material) was used [19]. 0.7% and 0.2% of patients were found to have an RTOG toxicity level of grade 3 and 4, respectively [9].

A similar study described the use of IGSRT in the treatment of 93 patients with 133 NMSC. Of the 133 NMSC lesions 67 were BCC, 17 were SCC, and 49 were SCC-IS. The cure rate was 99.2% and the Kaplan Meier (KM) local control rate was 98.95% at a follow-up of 2.57 years or 30.8 months. Initial energy and subsequent kV changes were selected by utilizing a combination of US imaging and clinical characteristics of the NMSC lesion. Measuring the tumor depth with US is important to treatment, as it allows the provider to select the proper penetrating energy to adequately treat the entire NMSC tumor. There were zero patients with an RTOG toxicity level of grade 3 or 4 [20].

Tran et al. reported a study using IGSRT to treat 1243 patients with 1899 NMSC lesions. Tumor types were as follows: BCC (51.7%), SCC (24.6%), and SCC-IS (23.4%). The cure rate was 99.7% and the KM LC/cure rate was 99.41% at maximum follow-up of 5 years or 63.6 months. HRDUS was performed prior to treatment, allowing determination of tumor breadth and depth, to select the proper width (field size), energy, and dose. Throughout the treatment course, US was performed at each treatment to make real-time modifications if needed. Energy selection and subsequent dose modifications were made on the basis of clinical and US imaging tumor characteristics, anatomic location, lesion depth, skin curvature, and histology. For larger, deeper, and higher risk tumors, higher doses per fraction and/or more fractions were recommended. The generally accepted premise is that most failures in NMSC lesions occur within 2–3 years, with a low likelihood of local recurrence for early stage NMSC after 2 years. This is supported by the identical 2- and 5-year absolute LC/cure rates of 99.41% which were observed in this study [10].

Moloney et al. updated and combined the two 2021 Yu studies, leading to the largest and longest published study utilizing IGSRT in the treatment of 1709 patients with 3050 NMSC lesions. The overall cure rate was 99.2% at a mean follow-up of 2.08 years. Cure rates by tumor type were BCC = 99.0%, SCC = 99.2%, and SCC-IS = 99.85. The KM LC/cure at maximum follow-up of 5.46 years or 65.56 months was 98.81%. The 5-year KM LC/cure rates by tumor type were as follows: BCC = 98.17%, SCC = 99.01%, and SCC-IS = 99.71% [16].

McClure et al. performed a retrospective cohort study in 2023, which compared the 2-year recurrence probability of 5391 early NMSC lesions treated by Mohs micrographic surgery (MMS) to 2286 early NMSC lesions treated by IGSRT. Pooled NMSC lesions treated by IGSRT showed a statistically significant improvement in 2-year recurrence probability compared to pooled lesions treated by MMS, with p < 0.001, and to lesions treated by MMS that were separated by histologic subtype, with SCC p < 0.001 and BCC p = 0.022 [21].

A retrospective cohort study performed by McClure et al. [22] in 2022 showed an improved overall 2-year recurrence probability of 2880 NMSC lesions treated by IGSRT to two studies with previously existing data on NMSC lesions treated with SRT. For IGSRT, McClure et al. found an overall 0.7% 2-year recurrence rate for all NMSC lesions (1.1% BCC, 0.8% SCC, 0.0% SCC-IS). In the SRT study conducted by Cognetta et al., they reported the overall 2-year recurrence rate of NMSC lesions was 1.9% (2.0% BCC, 1.8% SCC, 1.9% SCC-IS) [23]. In the other SRT study, Silverman et al. reported a 6.3% 2-year recurrence rate for BCC lesions [24]. For IGSRT, 2-year rates of recurrence are superior to these two previous SRT studies evaluating NMSCs across all histology in the former [23] and BCC in the latter [24]. This difference in recurrence rates was statistically significant (p < 0.001) [22].

In 2018, Stiegel et al. recognized a discrepancy between tumor subtypes seen in initial biopsies vs. intraoperative MMS sections. They noted that tumor subtype weighs heavily into the selection of treatment modality. A retrospective chart review of cases of NMSC referred for MMS was conducted over a 1-year period, recording changes between tumor subtypes observed at biopsy and those during MMS. They observed a substantial discrepancy between preoperative biopsy and intraoperative pathology, including a significant portion of tumors that became more aggressive. They reviewed 163 cases and found that 50.5% of tumor subtypes changed aggressiveness. Of these, 33% were more aggressive, whereas 17% were less aggressive. They concluded that treatment modalities without margin control may not provide adequate treatment for a considerable number of NMSC on the basis of tumor type alone [25].

This high rate of error of the initial biopsy to actual final aggressiveness (an extent of tumor involvement) may at least partially explain why excision without margin assessment has documented higher failure rates compared to Mohs. Similarly, it may in part account for the study findings showing traditional radiotherapy without HRDUS demonstrating statistically worse recurrence rates compared to IGSRT which uses HRDUS to assess tumor depth and extent [17, 18]. Prior to IGSRT, dermatologists had to make SRT treatment decisions based on NMSC pathology reports that Stiegel et al. confirmed are not giving us an accurate subtype 50.5% of the time in patients referred for MMS.

Shave biopsies typically include epidermis and some portion of the papillary or superficial dermis. Dermatologists often have two goals with regards to shave biopsy: diagnosis and favorable cosmesis. Given this scenario dermatopathologists can only diagnose the tissue that has been biopsied, which is limited by sampling error. Diagnostic accuracy of the tumor subtype is therefore limited by the depth of the shave biopsy technique. HRDUS benefits IGSRT because it reveals the width, depth, and morphology of the tumor that remains in the patient’s dermis after the shave biopsy. For example, if a biopsy pathology report tells us that the tumor is SCC in situ and the in vivo HRDUS image reveals a residual dermal tumor that is 1 mm in thickness, the in vivo HRDUS has confirmed the accuracy of that pathology report. If, on the other hand, a biopsy report tells us that a tumor is SCC in situ but in vivo HRDUS reveals a residual dermal tumor that is 3 mm in thickness, we need to adjust our diagnosis to reflect at least superficial invasion. The combination of biopsy pathology and in vivo HRDUS dermal visualization of residual dermal tumor clearly gives dermatologists a much higher level of diagnostic accuracy regarding tumor subtype. This high level of diagnostic accuracy and precise HRDUS tumor depth measurement prior to each dose of radiation is the most likely reason why IGSRT’s high cure rates are statistically superior to those of SRT or XRT.

Overall, these studies (Table S2 in the electronic supplementary material) demonstrate that IGSRT can consistently achieves ≥ 99% cure rates for NMSC in a dermatologic clinical setting, which is comparable and statistically superior on early analysis to cure rates achieved by MMS, with the educational support of an organized interdisciplinary team including dermatologists, radiation oncologists, medical physicists, and certified radiation therapists. Additionally, while MMS requires surgery to determine tumor depth, HRDUS can evaluate tumor depth in a non-invasive manner, without requiring surgery. While other non-invasive therapies for NMSC such as photodynamic therapy (PDT), topical 5-FU, and topical imiquimod can be useful, none of these can deliver the high cure rates of IGSRT or MMS. Further, topical applications require patient compliance for application, which could be jeopardized because of lack of clinician involvement.