INTRODUCTION

Non-melanotic skin cancers (NMSC) are the most common type of cancer in Caucasians. Increasing exposure to UV radiation is one of the most important etiological factors for the occurrence of these cancers. The vast majority of NMSCs consist of basal cell (approx. 80%) and squamous cell carcinomas (approx. the remaining 20%) [1].

Basal cell carcinoma (BCC) spreads locally, destroying normal tissue, and rarely metastasizes. However, if not treated successfully, it has the potential to destroy a large part of the face or invade subcutaneous fat, bone, and even the brain [2,3].

The association of BCC with UV radiation is less than that of squamous cell carcinomas as they often occur in non-photoexposed areas of the skin. 85% occur in the head and neck area, and 30% occur on the nose, which is the most common site of occurrence. It rarely occurs on the dorsal surface of the hands and may appear in non-photoexposed areas, such as the chest and genitals [1–3]. It occurs mainly in the elderly and in people with fair skin and affected by photoaging. The male-to-female ratio is 2:1.

Intermittent UVB radiation is thought to play the most important, although not the only, role in the development of BCC. Sites of previous injuries and scars are also areas where BCC may often occur.

Common types of BCC include nodular, superficial, micronodular, infiltrative, and sclerotic.

Squamous cell carcinoma (SCC) is a cancer of the keratinocytes and usually arises from the development of precancerous lesions. It is the second most common cancer in white people. It varies in aggressiveness depending on the degree of differentiation and the cause of its development, while unlike basal cell carcinoma, it metastasizes more frequently [2,3].

Clinically, it presents as a plaque or nodule with varying degrees of keratinization. Typically, poorly differentiated SCCs are soft to the touch without hyperkeratosis, while well-differentiated SCCs are hard and hyperkeratotic.

It is most common in people over 55 years of age and in Caucasians. In the U.S., it is estimated that 12 out of 100,000 men and 7 out of 100,000 women will develop SCC. There is a male predominance over women. Light skin types I and II and patients who have been exposed to ionizing radiation and phototherapy are at higher risk [1–3].

HPV viruses, especially types 16, 18, and 31, have been associated with squamous cell carcinoma. Other etiological factors include chronic immunosuppression (transplant recipients, HIV+), chronic inflammation (discoid lupus, chronic ulcers, scars, burns, etc.), exposure to industrial carcinogens, and chronic arsenic intake [2,3].

Common sites of squamous cell carcinoma are sun-exposed areas of the skin. The scalp in people with alopecia, the face, lips, earlobes, and the dorsal surface of the hands are common sites. SCC occurs more frequently on the lower legs in women than in men. It may also occur on the genitals [1–3].

It is estimated that, unlike BCC, where childhood burns and intermittent ultraviolet radiation are considered the main etiological factors, what leads to an increased likelihood of SCC is chronic exposure to UV radiation (e.g., outdoor work).

Numerous treatments have been employed to treat NMSC. These include surgical excision, cryotherapy, radiotherapy, photodynamic therapy, local and systemic medication, and others [4–6].

The treatment of choice is considered to be surgical excision of the lesions, especially Mohs surgery, with recurrence rates below 5% [4,5]. However, surgical excision is often not possible. Radiation therapy helps elderly patients who do not want surgical removal or who are not able to undergo it, due to other health problems, patients with lesions in areas of the face or neck where surgical removal will leave a poor aesthetic result, or patients with carcinomas in which the excision was not performed with healthy margins [7–20]. It is also used as an adjunctive treatment for high-risk tumors that were excised with healthy margins by Mohs technique but present significant perineural or nerve invasion. Common radiotherapy methods include superficial/photon radiotherapy (superficial RT/orthovoltage RT), electron beam radiotherapy (EBT), and brachytherapy [21–27]. This research will focus on superficial photon radiotherapy. Since the advent of Mohs surgery, there has been a decrease in the use of radiotherapy by dermatologists. However, radiotherapy is expected to become increasingly important in the coming years, due to the increasingly aging population [10,13,16].

Surgical removal of NMSC is not an option for many elderly patients, as complications are more likely in this population. Radiotherapy is a well-tolerated, simple, and relatively inexpensive treatment, given the photon energy delivered [25]. In superficial radiotherapy beams, the depth dose is rapidly reduced, allowing for dose limitation to healthy underlying tissues and is, therefore, indicated for the treatment of superficial tumors, such as NMSC [19,24, 28–45]. The usual total doses for the treatment of NMSC in the literature range from 40 to 60 Gy, with various fractionation schemes [46–49].

METHODS

The files of a total of 315 patients with non-melanoma skin tumors treated at the Radiation Oncology Unit of “Andreas Syggros” Hospital, from 2015 to 2021, were retrospectively analyzed. Files from 115 patients with BCC, from 137 patients with SCC, and from 62 patients with basosquamous (metatypic BCCs) (BSC) carcinomas were irradiated. All 115 BCCs were high risk without nodal involvement, and 65 of them were treated postoperatively either with positive margins (50) or perineural invasion (15). In regards to SCCs, all were high risk T1, T2, or T3 tumors without nodal or deep tissue involvement. 94 of them were primarily irradiated, out of which 69 with positive margins and 25 with perineural involvement. Two hundred patients (63.5%) were treated postoperatively, 75 (23.8%) were primarily treated with RT, and 40 (12.7%) were treated for local recurrence after primary surgical treatment. Patients were followed by the radiation oncologist and by the dermatologist for up to seven years after treatment. The follow-up time was defined as the time from the beginning of radiotherapy until the date of the most recent follow-up visit or death. Table 1 presents the details of patient characteristics.

RESULTS

The median follow-up duration was fifty months (range: 1–85). Thirty-two (32) relapses were observed. The total two-year recurrence-free rate was 91.1% (95%; CI: 87.2–93.9%). No further recurrences were observed after the period of 24 months. The respective two-year recurrence-free rates according to the indication group were 94.3% (95%; CI: 89.7–96.9%) for the postoperatively irradiated tumors, 89.2% (95%; CI: 79.5–94.4%) for the primarily treated group, and 78.8% (95%; CI: 61.9–88.8%) for those treated after local recurrence (log rank test; p = 0.0038) (Fig.1). Cox regression multivariate analysis revealed a hazard ratio (HR) of 4.5 (95%; CI: 1.76–11.51, p = 0.002) for the latent group, adjusted for age, sex, and histology. The results of the Cox regression analysis are shown in Fig. 1 and Table 2.

DISCUSSION

The largest series reports overall five-year cure rates of 91% to 93% for previously untreated BCCs. For patients with recurrent BCCs, the reported cure rates are somewhat lower, generally between 86% and 91%.

In the only randomized trial comparing surgery with radiotherapy in 347 patients with facial BCC < 40 mm, the primary endpoint was the failure rate (persistent or recurrent disease) after four years of follow-up. Among the 173 patients in the radiotherapy group, 55% were treated with interstitial brachytherapy, 33% were treated with contact brachytherapy and 12% with conventional radiotherapy. The four-year recurrence rate was 7.5% (95%; CI 4.2–13.1).

A systematic review and network meta-analysis of various treatments for BCC showed a 3.2% recurrence rate (95%; CI: 0.6–16.1%).

In a systematic review and meta-analysis of 20 observational studies and 1 randomized trial that included 3534 patients treated for cSCC of the head and neck, ART was associated with increased overall survival and disease-free survival (hazard ratio: 0.45; 95%, CI: 0.26–0.78; and hazard ratio: 0.52; 95%, CI: 0.33–0.84, respectively).

In phase 3, the randomized trial of ART with or without concurrent chemotherapy in patients with high-risk cSCC of the head and neck, high two-and five-year rates of freedom from locoregional relapse (88% and 83%, respectively) were achieved in radiation therapy alone.

In a series of 349 patients with advanced head and neck cSCC treated with surgical resection with or without ART, ART was associated with improved overall survival (HR: 0.59; 95%, CI: 0.38–0.90). For patients with PNI, ART was associated with improved overall survival as well as disease-free survival (HR: 0.44, 95%, CI: 0.24–0.86).

Patients treated for recurrent cancers have poorer locoregional control. Due to the advanced age of patients, more intensive treatment in order to achieve locoregional control is often poorly tolerated.

Radiation therapy remains a cornerstone in the management of non-melanocytic skin cancers, particularly BCC, cSCC, and Merkel cell carcinoma (MCC). Radiation therapy continues to provide excellent local control, cosmetic outcomes, and tolerability, especially in elderly patients or those with lesions in anatomically sensitive areas where surgery might be disfiguring or contraindicated.

In cSCC, radiation therapy has proven particularly effective as a definitive or adjuvant treatment, especially for high-risk tumors or those with regional metastases. This is consistent with case findings by Susel et al., who reported parotid metastasis from cutaneous SCC and highlighted the necessity of multimodal treatment to achieve disease control in advanced presentations [50]. Radiation therapy could be used postoperatively and as a definitive modality when surgery is not feasible.

The application of radiation therapy in MCC is well-supported in both our study and the literature. MCC, a rare but aggressive neuroendocrine carcinoma, is highly radiosensitive. As described by Abreu Velez et al., MCC must be distinguished from metastatic small-cell carcinoma, given its different origin and treatment pathway [51]. The high recurrence rate associated with MCC underscores the importance of adjuvant radiation therapy following surgical excision or as definitive therapy when surgery is contraindicated. Our findings align with current recommendations, showing excellent locoregional control with radiation therapy.

Our study also provides context for the role of RT in distinguishing and managing skin lesions secondary to systemic malignancies. Although not the primary focus of our analysis, reports such as those by Laabidi et al. and Corona-Herrera et al. describe rare cases of cutaneous metastases from prostate carcinoma and leukemia, respectively [52,53]. These cases emphasize the importance of accurate histopathological diagnosis in skin lesions and demonstrate the limited but meaningful palliative role of radiation therapy in metastatic disease.

Emerging therapies such as CAR-T cells are opening new avenues in dermatologic oncology, although they are still experimental in skin cancer management. Medina-Olivares discussed the expanding potential of these therapies and their integration with traditional modalities such as radiation therapy [54]. Future studies could investigate the synergistic effects of radiation therapy with immunotherapy or targeted agents, particularly in resistant or recurrent NMSC.

González-Torres et al. also emphasized the aggressive behavior and sarcomatous characteristics of MCC, reinforcing the importance of early intervention and combined therapeutic strategies [55]. Early radiation therapy, as part of a multidisciplinary treatment approach, can significantly improve outcomes in MCC patients.

CONCLUSION

Basal cell carcinomas may be well controlled with radiation therapy even when locally advanced. Squamous cell carcinomas have a poorer recurrence rate.

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