Role of radiotherapy in the treatment of lentigo maligna and lentigo maligna melanoma—a systematic review

Introduction

Background

Lentigo maligna (LM) is a melanoma in situ (MIS) subtype with an elongated radial growth phase that could become invasive, called lentigo maligna melanoma (LMM) (1). LM commonly occurs in the background of photodamaged and chronically sun-exposed areas, such as cheeks, nose, ears, scalp, and neck, and is related to cumulative UV exposure rather than intermittent (1,2). Globally, cases of LM/LMM constitute 15.7% of all cutaneous melanoma and are more prevalent in the older population of the seventh to eighth decades (1,3). Though not limited to older people, dermoscopic features of LM/LMM in younger populations show smaller and fewer than those of older people, thus making the diagnosis more challenging and requiring better diagnostic tools (4,5). In the United States, the Surveillance, Epidemiology, and End Results (SEER) data, showed an increment in the annual incidence of 2.42% for LM and 3.32% for LMM in 2009–2019. Moreover, the cumulative incidence of LMM after a 10-year follow-up of primary LM was 0.94% (3). The risk factors associated with LM occurrence include a previous history of skin cancer, solar lentigines, multiple actinic keratoses, fair skin, sunburns, and the least common association with melanocytic nevi. Several mimickers of LM/LMM can be difficult to distinguish, such as pigmented actinic keratosis, solar lentigines, seborrheic keratosis, and lichen planus-like keratosis (2,6,7). A study suggested that around 30–50% of LM cases develop into LMM (8). If left untreated, the latency period of LM might take up to 10–50 years (8,9).

Wide local excision (WLE) is a gold standard surgical procedure for LM/LMM. The lesion should be completely excised while preserving as much normal tissue as possible to prevent further recurrence (10). The legitimate margin for excision is still debatable because no randomized controlled trials (RCTs) are available, and only limited case series have reported the results. The recommended safety margin for excision is 5 mm, based on the 1992 consensus guideline (11). However, several studies suggested that a 5-mm margin was inadequate in several melanoma-in-situ (MIS) cases, and inadequate excision increased the risk of recurrence (12-15). A more recent study suggests that preferable pathological margin of ≥4 mm should be considered for management of MIS patients who receive standard surgical treatment, as it may reduce the local recurrence and mortality by 4.8% and 4.6%, respectively (16). Perioperative clinical examination utilizing dermoscopy or reflectance confocal microscopy (RCM) and pathological examination through biopsy is important to mark the adequate margin of ≥5 mm for excision (range, 5–10 mm) (12,17). Compared to the conventional method (visual + dermoscopy), RCM offers superior outcome for improving tumor clearance and unnecessary tissue removal because it can detect the subclinical margin by 92% (5). For LMM, a safety surgical margin of 10–20 mm with or without sentinel lymph node biopsy, depending on tumor thickness, is recommended for other subtypes of invasive melanoma (10,18,19).

Several factors might affect the option of surgery for the treatment of LM such as location, advanced age, patient’s comorbidities, or preference (2). Therefore, better options might be non-surgical management such as radiotherapy, topical imiquimod, laser, azelaic acid, 5-fluorouracil cream, and cryotherapy (20). A systematic review showed that radiotherapy had a lower recurrence rate (range, 0–31.3%; mean 11.5%) compared to topical imiquimod (range, 4.2–50%; mean 24.5%) and laser treatment (range, 0–100%; mean 34.4%) (21). Meanwhile, cryotherapy demonstrated highly variable outcomes, with recurrence rates ranging from 0–40% across different studies (22-24). A 10-year follow-up study of Grenz ray for LM/LMM management reported clearance rate of up to 97% (25). In contrast, topical imiquimod which is used off-label for MIS, particularly LM and LMM, gives more moderate results. A recent review reported a clinical clearance rate of 43.2%, with a recurrence rate of 9.4% following treatment (26). Similarly, another review demonstrated a complete response in 59% of cases, with 18% of relapse rate post-treatment (27). Thus, the role of radiotherapy in LM/LMM treatment, either as primary or adjuvant therapy, provides superior outcomes compared to other approaches.

Rationale and knowledge gap

Since then, many retrospective studies with various radiotherapy techniques have reported the clinical outcomes of primary and adjuvant radiotherapy for LM/LMM (28-34). Despite multiple publications regarding the technical parameters, including total dose, radiation energy, number of fractions, and fractionation schedules. There are still no specific guidelines for radiotherapy treatment of LM/LMM. The diversity of these parameters could cause variability in tumor control and different biological effects on normal and cancerous tissue damage. To date, no study has systematically analyzed the biological impact of these varying protocols using a biologically effective dose (BED) model to correlate them with clinical outcomes in LM/LMM.

Objective

Therefore, this study aims to systematically review previous literature and discuss the effectiveness of different radiation treatment regimens and clinical outcomes in terms of complete response rate (CRR), clinical regression, local recurrence rate (LRR), metastatic rate (MR), and chronic skin toxicity by comparing their BED. We present this article in accordance with the PRISMA reporting checklist (available at https://tro.amegroups.com/article/view/10.21037/tro-24-39/rc).

Methods

Search strategy

We conducted the literature search from July 24, 2024 until August 11, 2024 through several appointed electronic databases (PubMed, Scopus, and Cochrane Library). The last search was conducted on August 4, 2024 for the Cochrane Library and August 11, 2024 for PubMed and Scopus. The first and second authors independently performed the article search. The keywords for the literature search were: “lentigo maligna”, “lentigo maligna melanoma”, “Hutchinson”, “radiotherapy”, “Grenz ray”, “X-ray”, and “radiation therapy” with the additional Boolean operators such as AND and OR, as listed in Table S1. Studies included in this review were published from 1976 until 2020. We also checked through lists of bibliographies from previous reviews to find more relevant studies for additional information to ensure a comprehensive literature search.

Inclusion and exclusion criteria

The selection process is summarized in Figure 1. The studies were evaluated and included if they met the following criteria:

Figure 1 PRISMA flow diagram of search flow.

Inclusion criteria

The inclusion criteria for this review required original articles written in English, and those articles contained information on the results of the use of primary radiotherapy alone or in combination with other modalities for LM/LMM that had been confirmed clinically or histopathologically. Any studies that evaluated more than one form of therapy (e.g., surgery, laser treatment, topical treatment, etc.) were also included. However, we only extracted data on radiotherapy. We also considered prospective and retrospective studies such as case series, cohort studies, and trials. Articles with overlapping patient groups were assessed and included if the sample size was larger than the anothers.

Exclusion criteria

Review articles, single case reports, editorials, letters, and book chapters were excluded from this study. Other exclusion criteria were incomplete data in the article, proceedings, and unfinished trials.

Data extraction and synthesis

The main supporting data, extracted from the appointed studies, consisted of the CRR, disease clinical regression, local recurrence, metastasis, radiation dose, fractionation, and cosmetic results, including skin reactions. The two authors evaluated those studies that fulfilled the inclusion criteria independently, and further analysis of the studies was discussed with the third and fourth co-authors. In this review, we calculated the BED value of each regimen from the studies to observe the biological effect of radiation on the tissues, including the value of early and late responding tissue. We compared the results with the clinical outcomes to explore which radiation regimen was the most compatible for LM/LMM patients regarding their BED values.

Quality assessment

We evaluated the quality of the selected studies by using the Newcastle-Ottawa Quality Assessment Scale (NOS) (35). The first author performed the quality assessment and presented the results to co-authors for discussion in any disagreement. This NOS scale is an instrument to assess the quality of non-randomized studies, such as cohort or case-control studies, in terms of systematic review or meta-analysis writing. Three criteria must be evaluated for quality: selection, comparability, and outcome; each criterion has further subcategories allowing more detailed assessment. In the selection criteria, we assessed the representativeness of the exposed cohort, selection of the non-exposed cohort, ascertainment of exposure, and demonstration that outcome of interest was not present at the start of the study. As for the comparability criteria, comparability of cohorts on the basis of the design or analysis is evaluated. Furthermore, the outcome criteria analyze the assessment of outcome, follow-up period, and adequacy of follow-up of cohorts.

Statistical analysis

We conducted a systematic and independent literature search according to the PRISMA guideline. In this review, the BED, including the early and late responding tissue, of each regimen from the studies was calculated to observe the radiation effect on tissues. We compared the results with the clinical outcomes to explore which radiation regimen is the most suitable for LM/LMM patients. BED was calculated as BED = n × d [1 + d/(α/β)] using α/β =10 Gy for early-responding tissues and α/β =3 Gy for late-responding tissues and tumors. The acute skin reaction due to radiation was observed and compared with the result of the BED value of early responding tissue. Since LM is a type of melanoma with wide confidence intervals and low α/β ratio (0.6–2.5 Gy), it was categorized as having a BED value of late responding tissue, with the α/β ratio of 3 Gy, as the BED of the tumor itself (36). Therefore, the other clinical outcomes (e.g., CRR, clinical regression, MR, and LRR) and any chronic skin reactions were evaluated by comparing the result of the BED value of late-responding tissue.

Results

Study characteristic

During the initial search through electronic databases, we found 416 articles related to the keywords. After excluding the duplicates, 364 articles were screened by the title and abstract content, resulting in 339 articles being excluded. The reports assessed for eligibility were 18 articles after leaving 7 articles not retrieved. The seven articles did not meet the predetermined criteria because two articles were incomplete, and five articles were unavailable. Next, the full-text articles were examined independently and were included if they met the inclusion criteria. Thus, the overall reports in this review were 10 reports (Figure 1) (28-31,33,34,37-40). The main characteristics of the included studies are summarized in Table 1. The studies were published between 1976 and 2019 and were mostly conducted in Europe (n=5) (28-30,39,40) followed by Canada (n=3) (31,34,38), Australia (n=1) (37), and the United States (n=1) (33). In total, there were 988 LM/LMM patients included in this review and the overall average sample size was 98 patients.

Quality assessment of included studies

The NOS scale evaluates the reliability of a study and identifies the risks of bias, especially for non-randomized studies (Table 2). Three studies were considered as good, with strong methodological quality and low-risk bias (34,38,39). However, the other seven studies were of low quality, despite all included studies being observational cohort designs (28-31,33,37,40). Moreover, they had no explanation of the selection of non-exposed cohorts, thus, no comparability in the studies. There was a scarcity of RCTs focusing on LM/LMM in conjunction with radiation therapy. Therefore, it resulted in high-risk bias.

Treatment modalities and patient characteristics

Female participants outnumbered male patients in most of the studies. The average female and male ratio in this review was 1.7:1. Moreover, most patients were categorized as elderly, with the overall mean of patients age being 71.9 years old. A total of 886 LM and 107 LMM lesions were treated by radiotherapy. Most lesions were distributed in the head and neck region. The size of LM lesions was mostly below 5 cm, but there was one LM patient in the study of Christie and Tiver (37) who had a larger size (9 cm). For LMM lesions, the thickness varied, ranging between 0.17 and 10 mm. The clinical outcomes of patients after radiotherapy were assessed and followed around 15–96 months (mean or median) after treatment. The energy range of X-ray radiation used in the studies varied. The lowest X-ray energy was 10 kV, whilst the highest was 250 kV. Around 82.7% of patients received treatment with a range of modality energy between 10–20 kV, 17% treated with energy of 20–250 kV, and 0.3% with both modalities.

Radiation dose, fractionation and safety margin

The range of total radiation dose given in this review was 12–160 Gy (10–20 kV) and 35–57.5 Gy (20–250 kV). Respectively, the treatment was administered in 3–13 fractions from daily to 5-day intervals and 5–23 fractions from daily to 4-day intervals. All studies’ safety margins for radiation therapy ranged from 5–20 mm.

BED value

The calculation of BED value was categorized based on early and late-responding tissue, distinguished by the difference of α/β ratio. The BED of early and late responding tissue varied from 17–587 and 28–1,584, respectively.

Comparison of BED value and clinical outcomes

The overall outcomes (e.g., CRR, LRR, MR) of each included study in this review are presented in Figure 2. Those categories, followed by clinical regression, cosmetic results, and skin reactions, were compared with the tumor BED value, as provided in Table 3.

Figure 2 Distribution of the overall outcomes of LM and LMM patients. CRR, complete response rate; LM, lentigo maligna; LMM, lentigo maligna melanoma; LRR, local recurrence rate; MR, metastatic rate.

CRR

Most of the CRRs in all studies reached more than 87% for both LM/LMM patients (Figure 3). Studies that utilized the X-ray radiation energy of 10–20 kV (28–30,33,39,40) showed that the Schmid-Wendtner et al.’s study (14.5 kV) had the highest CRR (CRR =95% overall; 100% LM and 86% LMM patients) among other studies, in which the tumor BED value was 433 Gy₃ (28). In the study by Kopf et al. (12 kV), the BED value was higher (BED =767 Gy₃) compared to the latter, with a slightly lower result (CRR =94%) (33). On the other hand, Hedblad and Mallbri’s study (10 kV) resulted in a wide range of tumor BED values (BED =657–1,584 Gy₃) but reached only 88% of the CRR of both LM/LMM patients. In their study, the CRR increased gradually along with the increment of BED value. A total dose of 150 Gy (BED =1,400 Gy₃) yielded a CRR of 93% across all patients. However, increasing the BED value beyond this point led to a decrease in CRR (30).

Figure 3 Overall distribution of CRR with the BED value. BED, biologically effective dose; CRR, complete response rate.

In studies that operated 20–250 kV X-rays (29,31,34,37,38), the lowest CRR of LM patients was achieved by Lee et al. (CRR =87.1%), which utilized a 150 kV X-ray, with the lowest tumor BED value (BED =92 Gy₃) (38). Compared to other studies, Christie and Tiver (100 kV) reached the perfect CRR (CRR =100% among all five respondents of LM patients) with BED value of 103–105 Gy₃ (37). Tsang et al. and Harwood reached the CRR of 89% and 90%, respectively, for LM patients with similar tumor BED value (BED =106–117 Gy₃) (31,34). Additionally, the CRR of LMM patients in Harwood’s study revealed 92% of patients had a complete response to the treatment (31).

Clinical regression

Several studies that stated the complete regression of LM/LMM after radiotherapy showed quite different results. Schmid-Wendtner et al. utilized 14.5 kV of X-ray radiation with a total dose of 100 Gy (in 10 fractions) for radiation treatment, resulting in a high tumor BED value (BED =433 Gy₃) (28). Meanwhile, studies by Harwood (100 kV; 120–175 kV) and Christie and Tiver (100 kV) showed the range of tumor BED values from 106 to 117 Gy₃ and 103 to 105 Gy₃, respectively (31,37). A higher BED value, as in the Schmid et al. study, showed a shorter time required for LM/LMM to be completely regressed (maximum in 8 months), while other studies with lower BED value provided longer periods of clinical regression (maximum 15 months for LM, and 24 months for LMM) (28,31).

LRR

The overall LRR throughout all studies was 12.2% (Figure 4). For studies that used 20–250 kV X-ray radiation for the treatment (29,31,34,37,38), the highest LRR was presented by the Lee et al. study (LRR =29%), with the lowest tumor BED value (BED =92 Gy₃). The average size of the lesion was 2.63±1.32 cm (38). A study by Christie and Tiver (100 kV) reported that no patient had local recurrence after radiation therapy, which showed the BED value of 103–105 Gy₃ (37). Meanwhile, the study of Farshad et al. achieved the highest BED value among other studies (BED =126–162 Gy₃) with an overall LRR of 7%, in which 50% of these patients were treated by lower energy of 20–50 kV X-ray. Besides, in the Farshad et al. study, most patients who received this treatment were LMM with tumor thickness of >3 mm (29).

Figure 4 Overall distribution of LRR with the BED value. BED, biologically effective dose; LRR, local recurrence rate.

Furthermore, for 10–20 kV X-ray radiation treatment (28-30,33,39,40), a study by Schmid-Wendtner et al. (14.5 kV) showed the lowest overall LRR (LRR=3%) with tumor BED value of 433 (28). Meanwhile, the highest LRR was achieved by Kopf et al. (LRR =31%), which used 12 kV X-ray (33). The BED value was 767 Gy₃, which was higher compared to the previous study. The overall distribution of LRR with the BED value can be seen in Figure 3.

MR

Comparing studies with 10–20 kV X-ray radiation energy (Figure 5) (28-30,33,39,40), a study by Zalaudek et al. (10 kV) in 15 LM patients reported no metastasis occurred (39). This study showed a relatively high BED value of 920 Gy₃. On the contrary, the highest MR occurred in a study by Kopf et al. (12 kV), which reached 19% of LM patients with a lower tumor BED value (BED =767 Gy₃) (33). Despite the lower BED value in the Kopf et al. study, Schmid-Wendtner et al. (14.5 kV) showed no metastasis among LM patients and 4.5% LMM patients with metastasis, thus, giving overall MR was only 1.5% with the lowest BED value (BED =433 Gy₃) among other studies within the same range of X-ray energy (28).

Figure 5 Overall distribution of MR with the BED value. BED, biologically effective dose; MR, metastatic rate.

The data on studies with higher X-ray radiation energy (20–250 kV) were limited (29,31,34,37,38); only three studies reported the results (29,31,34). The study by Harwood and Farshad et al. reported the same overall MR among LM/LMM patients with slight differences in their BED values (BED =106–117 Gy₃; BED =126–162 Gy₃, respectively) (29,31). Moreover, as for LM-only patients, Tsang et al. reported no metastasis with the same BED value as Harwood (34).

Skin toxicity

The cosmetic results on the skin after radiation therapy were predominantly fair to excellent (28-31,33,34,37-40). The highest range of BED value for early responding tissue (BED early =267–587 Gy₃) at 10 kV of X-ray showed that 2% of patients experienced acute severe reactions due to irradiation. This was followed by a high value of BED for late-responding tissue (BED late =657–1,584 Gy₃) and serious chronic skin reactions that occurred (e.g., skin pallor, telangiectasia, and macular hyperpigmentation) (30).

The study by Lee et al. indicated the BED values for early and late responding tissues at 63 and 92 Gy₃, respectively, with 150 kV of X-ray. The acute and chronic effects on the skin varied: 19.4% developed telangiectasia, 6.5% experienced erythema, and 6.5% had hypopigmentation (38). Other studies with the same X-ray energy range also showed similar reactions with little difference in their BED values.

Discussion

Radiotherapy for the treatment of LM and LMM has been widely used, either as primary or adjuvant therapy, because, for some patients, surgery is contradictory to their conditions (11,41). Before starting the treatment, several factors must be considered to get the most benefit from radiation treatment, such as patient factors, tumor factors, and treatment factors. Moreover, dose fractionations and preserving as much normal tissue as possible during treatment are fundamental to ensure patients’ quality of life (42). There are a lot of reports explaining the use of radiation therapy for the management of LM/LMM. Thus, many variations of treatment parameters are utilized in each report. Due to many differences in technical parameters and no specific guideline stating the exact method, we conducted this systematic review to compare the methods from each study and evaluate the outcomes by considering the BED value of each method, which is the distinction from the previous reviews.

Generally, this review’s evidence of radiotherapy treatment was limited to non-randomized trials, case series, and case reports. There are 988 patients with completed follow-ups extracted from 10 selected studies. Most patients were categorized as elderly in this review (age mean 71.9 years old), with females being the most prevalent gender (1.7:1). Other studies also mentioned a similar ratio between both genders (30,43). Besides, women are detected as 2 to 3 years older at diagnosis. Compared to other types of melanomas, LM/LMM are commonly found in elderly patients, at which the mean age of diagnosis is 66–72 years (43,44). However, the number of cases has been rising over the decades, and the age of diagnosis has shifted to the younger population (44).

The regimen of radiation therapy varied among included studies, starting from Grenz ray (10–20 kV), contact therapy (40–50 kV), superficial therapy (50–150 kV), and orthovoltage therapy (150–500 kV) (45). In general, the outcome of radiation therapy is promising and effective for patients for whom non-surgical treatment is more favorable (25,46). This review’s overall CRR reached up to 86–100%, and crude analysis of LRR was 12.2% of all patients. Moreover, the range of MR was 0 to 19%. Other methods, such as laser treatment and topical imiquimod, have higher recurrence rates and lower CRRs than radiotherapy (21,26,27). The recurrence rate was 24.5 and 34.4, whereas the CRR was 50–93% and 54.5–100% for topical imiquimod and laser therapy, respectively (21). Thus, radiotherapy is better in high-risk patients while considering other treatments for adjuvant therapy.

Although there were several incomplete data on CRR, predominantly, a BED value of 433–1,400 Gy₃ established a CRR value of more than 90% and an LRR of less than 31% in studies utilizing 10–20 kV X-rays. Schmid-Wendtner et al. had the highest overall CRR (CRR =95%) and lowest LRR (LRR =3%) of all studies, while the BED value was lower than the other (BED =433 Gy₃). Compared to other studies, Schmid-Wendtner et al. used higher energy for the treatment (14.5 kV) and prescribed a depth dose of 50% at 1.1 mm, which was effective for treating in-situ melanoma, especially LM. Despite this, the CRR of LMM patients alone in their study was 86%, even though they had surgery to remove the nodular part (28). Theoretically, the radiobiology characteristic of this X-ray will constrain the doses in the epidermis or dermis per se (no deeper than 2 mm) (21,25). Besides, Grenz ray should not be used if the tumor extension depth exceeds 0.8 mm or LM occurs in skin appendages because the dose would decrease exponentially with distance, and penetration would not be sufficient (25,30,42). Since LMM is more invasive than LM, a higher energy X-ray would be required to penetrate more into the cancerous tissue for an optimum result (47). Furthermore, when juxtaposed with other studies that utilized 20–250 kV X-ray, a BED value of 103–240 Gy₃ achieved similar results in an overall CRR of over 90% but with LRR of less than 11% for both LM and LMM. Harwood used 100 kV and 125–175 kV X-rays (BED >100 Gy₃) to treat LM and LMM patients, respectively, and prescribed a depth dose of 50% at 6 mm, resulting in an overall CRR of 91% (90% LM, 92% LMM) and LRR of 9% (31). Compared to the lowest CRR and highest LRR in the study by Lee et al., they prescribed a total dose of 50 Gy in 20 fractionations (BED =92 Gy₃) with 150 kV X-ray (38). Although differences in energy utilization during treatment could affect dose penetrance into the tissue, the BED value still determines the effect on tissue. Besides, the total dose and fractionation will also influence the outcome, especially in tumors with a low α/β ratio (48,49). Unfortunately, the comparison between BED values and the outcome of melanomas is still rare. In other cases, a study that highlighted BED values on breast cancer showed differences in recurrence rate. Yamada et al. reported two BED values: 65 Gy₄ (50 Gy/25 fractions) and 75 Gy₄ (40 Gy/16 fractions). The result of the recurrence rate was 12.7% and 6.8%, respectively. However, this result was not statistically significant even though the higher BED offered a smaller recurrence rate (P=0.09) (50). Moreover, a higher BED value (BED ≥180) also benefited from higher recurrence-free survival in patients with prostate cancer (51).

The relation between BED values and MR varied among all studies. Even though the value was higher than the other, the MR would not be lower as predicted. In 10–20 kV X-ray, the range of MR was 0–19%, while the other studies ranged 0–2%, with 20–250 kV X-ray. Studies with higher radiation energy exhibited favorable outcomes in terms of MRs compared to lower energy studies. This is because higher radiation energy yield deeper penetration which allows deeper tissue coverage (52). However, a contradictory finding was found in the study by Kopf et al. where the BED value was relatively high (767 Gy₃), with the highest MR (19% among LM patients) and highest LRR (31% among LM patients) (33). Meanwhile, Schmid-Wendtner et al. had no metastasis nor recurrence of LM patients with a lower BED value (433 Gy₃) (28). Compared to other studies with similar energy categories, the study by Kopf et al. utilized a relatively low energy setting (12 kV) and a total dose of 100 Gy (BED 767 Gy₃). This contrasts with findings from other studies that reported higher BED value (920–1,584 Gy₃) while still using low-energy Grenz rays (10 kV), such as those by Hedblad and Mallbris and Zalaudek et al., which demonstrated better tumor control (30,39). Conversely, studies by Farshad et al., Schmid-Wendtner et al., and Lazarevic et al. employed higher energy (12–20 kV) but delivered lower BEDs (162–489 Gy₃) and still achieved favorable outcomes (28,29,40). As mentioned previously, this finding suggests that radiation energy plays critical role alongside dose intensity in ensuring effective treatment. The biological impact of radiation exposure is highly affected by several measures such as the amount of absorbed dose, the dose rate of exposure, and total area or volume of exposure (53). Moreover, individual factors, such as age, gender, comorbidities, genetic factors, and immune health systems, may significantly affect treatment outcomes (54). Therefore, while higher BED improves biological effect, it is essential to recognize that multiple patient-specific and treatment-related factors can influence the ultimate therapeutic effect. Besides, the study by Kopf et al. utilized a non-standardized radiation device with modification intended to approximate Grenz ray output, raising concerns regarding treatment consistency and comparability with other studies (33). Therefore, the study by Kopf et al. likely failed to achieve suboptimal tumor control, resulting higher metastasis and recurrence rates. Furthermore, according to in vitro studies, sublethal radiation may increase the risk of metastasis (48,55). The sublethal dose causes the regrowth of the primary tumor, which can cause an increase in the MR due to increased hypoxic fraction and hypoxia-induced up-regulation of the urokinase-type plasminogen activator receptor (uPAR). The irradiated tumor usually has a higher risk of regrowing, especially with inadequate radiation therapy, than the untreated tumor due to the induction of hypoxia after irradiation (55). Moreover, since melanoma has a low α/β ratio and wide confidence interval, it will also influence the sensitivity of the tumor toward radiotherapy and may cause sublethal effects on the cancer (36). Thus, to minimize metastases, high doses per fraction that result in high BED values can alter the radiosensitivity of malignant melanoma and are effective as the treatment (48,56).

High-value BED typically relates to a greater likelihood of tumor complete regression. As seen in the study by Schmid-Wendtner et al., both LM and LMM patients had complete regression of the lesion around 2 to 8 months (14.5 kV; BED =433 Gy₃) (28). Better representation can be observed between studies with higher energy X-rays (20–250 kV), higher BED values resulted in a shorter median time for the disease regression. Based on the results in this review, the duration of disease regression prolongs when the BED value decreases. The nature of BED represents the optimal radiation dose for achieving an effective biological impact on the cell. Thus, a higher value will cause more DNA damage to the targeted cells (48). A study in 2000 reported that higher BED value improved tumor local control of epithelial skin cancer. A low BED value significantly increased the local failure of the tumor [hazard ratio (HR) =1.76, 95% confidence interval (CI): 1.07–2.88] (57). In different cases, a linear correlation between higher BED and tumor volume changes was significant in patients with vestibular schwannomas during stereotactic radiosurgery (SRS) (58).

Even though a higher BED value is desirable for tumor control, especially melanomas that have low α/β ratio, minimizing potential skin toxicities must be considered. In this review, most studies had good to excellent outcomes regarding skin reactions after irradiation (28-31,33,34,37-40). Acute skin reactions usually occur in cells that have a higher α/β ratio and vice versa (59). According to the results, most studies reported patients with acute skin reactions with each BED value of early-responding tissue. The most common acute skin reactions in this review were erythema and desquamation (34,37,38). Erythema usually occurs as the earliest reaction after exposure to high-dose radiation, which will resolve within hours. These signs are commonly observed in Grade 1 radiation dermatitis (1,59). Studies with BED values of >433 Gy₃ (with 10–20 kV X-rays) and >92 Gy₃ (with 20–250 kV X-rays) are exposed to more evidence of chronic skin reactions such as hyper/hypopigmentation, telangiectasia, skin pallor, and skin pigmentation. In the study by Farshad et al., around 43% of patients developed other skin malignancies, 3% developed internal malignancies, and 90% had the primary LM/LMM lesion on the face region (29). Secondary malignancy is not an unusual late complication after radiation (59). Approximately 15% of cases will develop secondary malignancies after head and neck irradiation in 5 years (60). Therefore, the implementation of patient monitoring protocol for acute and chronic skin reaction and secondary malignancy risks in LM/LMM patients must be highly considered, especially those with facial lesions.

Limitations

Despite the relevant insights presented in this review, several limitations should be addressed. These limitations could influence generalizability and results interpretation. The key limitations of this study include incomplete data, and a few studies have compared BED values with outcomes of skin malignancies.

According to the quality assessment results, most of the studies were categorized as having high risk of bias. Moreover, the detailed dose information was not available in several studies. Instead, they listed a range of total doses. Therefore, the calculation of the BED value was done in a range format, making it difficult to perform precise comparisons among studies. We also wanted to assess the accuracy of the dose with tumor size by reflecting on the BED value with the measured clinical outcome. However, there were inconsistencies in reporting data on tumor size. Not only that, but several key information was also lacking in a few studies, such as data on CRR, MR, and clinical regression. Furthermore, there was a lack of elucidation on how many patients with LM and LMM were excluded during the follow-up process. These limitations may impact the ability to draw firm conclusions on clinical outcomes and introduce bias in the analysis of long-term outcomes.

Conclusions

As a non-surgical treatment, radiotherapy has become a better option for LM and LMM patients where surgical intervention may not be feasible. The BED is critical in influencing clinical outcomes. In this review, higher BED values, either low-voltage (10–20 kV) X-rays or higher-voltage (20–250 kV) X-rays, generally correlate with better CRR, lower LRR and swifter disease regression, though individual results can vary depending on tumor type and characteristics. Despite maintaining a high BED value, careful consideration of giving an adequate total dose is crucial in managing potential recurrence, metastasis, and serious complications, especially in melanomas with low α/β ratio. Thus, further research is warranted to establish standardized guidelines and explore the long-term implications of treatment.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://tro.amegroups.com/article/view/10.21037/tro-24-39/rc

Peer Review File: Available at https://tro.amegroups.com/article/view/10.21037/tro-24-39/prf

Funding: None.

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