Radiotherapy has been used for decades as non-invasive alternative for patients with LM and LMM who are not amenable to surgical resection [7] and is – particularly for LM – listed as a treatment option in current melanoma guidelines [4, 24]. Radiotherapy is typically used in patients where surgery may result in poor functional or cosmetic outcomes or if there is an increased surgical risk due to patient age, comorbidities or medications such as anticoagulation [1]. However, all evidence for the use of radiotherapy to treat LM and LMM comes from retrospective patient series. Our review summarizes all available studies from the last 50 years and found 14 eligible studies.
Reviewing 14 retrospective patient series with treatment of a total of 1243 lesions by either Grenz rays or superficial X-rays, recurrence rates from 0 to 31% were reported. The greater part showed “good” to “excellent” cosmetic outcome, but long-term skin changes were reported in up to 20%.
The majority of eligible studies on radiotherapy for LM and LMM had recurrence rates which are comparable to surgical resection [6] and more favorable than studies on other non-invasive treatments such as laser therapy or topical immunomodulatory therapy with imiquimod [6].
In contrast to previous reviews [5, 6], we have included more recently published patient series [10, 11] as well as publications in German [20, 22, 23] with special focus on radiotherapy techniques and fractionation. Also, we reviewed radiotherapy outcomes for LM as well as LMM, as many publications report on both patient groups [11, 12, 15, 16]. Both patients with LM and LMM admitted for radiotherapy are likely to have similar characteristics such as large overall lesion size (invasive and noninvasive components), advanced age and comorbidities favoring non-surgical therapeutic approaches. The results of the presented patient series confirm that radiotherapy for LMM with or without previous excision of nodular components provides low recurrence rates [11, 15]. Congruently, the 2019 European consensus-based interdisciplinary guideline for malignant melanoma lists radiotherapy as treatment option for inoperable LMM in addition to LM [4].
Radiation techniques and outcome
Our results show that a wide range of dose prescriptions and fractionations have been used for the treatment of LM and LMM.
In general, treatment techniques can be divided into Grenz ray therapy and superficial radiotherapy. Grenz rays generally have an energy range from about 10 to 30 kV and are at the lower end of the X-ray spectrum. Grenz rays have a very low tissue penetration with a half-dose depth of about 1 mm. Superficial X-rays are generally considered to have an energy range from 30 to 150 kV, but specifications of this range vary a lot. Their half-dose depth can be more than a centimeter. Other available techniques such as megavoltage photons, electrons or brachytherapy are also available for cutaneous tumors such as LM and LMM [1, 25], but have not been used in the reviewed studies. However, brachytherapy moulage techniques [26] or linac-based intensity-modulated radiotherapy [27] may be good therapeutic options particularly in case of extensive scalp lesions.
Due to the low tissue penetration depth, Grenz ray radiotherapy with low beam energies (9–14.5 kV) can be safely performed with total doses of at least 100 Gy (corresponding approximately to 10,000 R in earlier series) with a single fraction dose of 10–20 Gy.
Superficial radiotherapy was more commonly applied with smaller single fractions of 2.5–7 Gy and lower total doses.
A preferred fractionation schedule or a dose-response relationship cannot be identified based on the available studies. For Grenz ray therapy with up to 15 kV photons, a therapeutic regimen with single fraction doses of 10–20 Gy and total doses above 100 Gy, is highly effective and safe, but this regimen should never be translated to higher Grenz ray energies, to superficial X-rays or to other modalities with deeper tissue penetration due to the risk of excessive toxicity. For superficial radiotherapy, biologically equivalent doses to 54–60 Gy in 2 Gy per fraction have been recommended for primary radiotherapy for LM [1]. As protracted normofractionated treatment regimens impose logistical problems on the typically elderly and comorbid patient presenting with LM or LMM, hypofractionated schedules with doses of 2.5–4 Gy per fraction are generally favored in clinical practice, although doses up to 7 Gy have been reported [18].
The radiation field in the treatment of LM and LMM typically includes the visible lesions with a safety margin of 5–20 mm of the surrounding skin to account for microscopic disease extension. Although data is limited, it has been suggested that smaller margins may result in an increased risk of out-of-field recurrences [7]. If anatomically possible, a margin of at least 10 mm from the visible lesion to the field edge is recommended [1]. Additionally, pre-treatment mapping biopsies or in-vivo reflectance confocal microscopy may help to assess the extent of the lesion in selected cases [4].
There have been concerns that Grenz ray therapy with a half-dose depth of approximately 1 mm may provide insufficient dose coverage of LM extending into skin appendages (e.g. hair follicles), skin folds or for clinically inapparent LMM components. However, case series demonstrate that Grenz ray therapy can achieve high local control rates of approximately 90% or more at experienced European centers despite these concerns [10, 12]. In contrast, Grenz ray treatment was abandoned in a US center after a recurrence rate of nearly one third [21] which may be due to too small margins, a half-dose depth of less than 1 mm and potential quality assurance issues [7].
Outside of centers experienced in low energy Grenz ray therapy, we support the opinion of Fogarty et al. [1] to favor superficial radiotherapy or at least higher Grenz ray energies for LM and LMM which allow a complete coverage of the target volume (including skin appendages) with the therapeutic dose. Additionally, superficial X-rays are likely to result in less dose inhomogeneities in skin areas with concave or convex surfaces.
As already stated previously, there is a trend that radiation oncologists prefer superficial RT techniques whereas Grenz ray therapy is more commonly used by dermatologists [7].
Pigmentations have disappeared within one to 24 months after the end of the treatment. It is generally recommended to assess pigmentation clearance 6 months after radiotherapy [1]. Recurrences were reported within three to 108 months which highlights the need of follow-up visits after radiotherapy.
Cosmetic results
Overall, most series report favorable cosmetic outcomes for RT for LM and LMM. Common late adverse effects included hypopigmentation, teleangiectasia and skin atrophy comparable to radiotherapy series for other skin neoplasms. However, the rate of late adverse effects may be underestimated by the retrospective nature of all included studies without systematic assessment of toxicity in most cases. Late effects of radiotherapy are generally highly dependent on the specific dose and fractionation regimen as well as on the field size and localization of the target area [28]. Based on the available evidence, it has been suggested that cosmetic results in LM radiotherapy may be more favorable with Grenz rays compared to superficial X-rays [6]. Given the relatively high average age of patients with LM or LMM treated with radiotherapy, long-term adverse effects may be less relevant for the choice of the therapeutic modality.
Notably, no radiation ulcers or fibrosis were reported. Finally, the risk of second cancers induced by radiotherapy is likely to be negligible in this elderly patient population and was not reported by any study.
Limitations
An essential limitation of our review is the low level of evidence for radiotherapy of LM and LMM. All studies using radiotherapy were retrospective and from single institutions, and the majority did not report on other treatment options such as surgery or imiquimod. Additionally, some studies included LM which was only detected clinically without biopsy, and treatment techniques as well as recurrence rates were not reported consistently. According to a recent Cochrane systematic review, data quality is a major issue for any treatment option for LM [4].
The comparison of therapeutic alternatives and their outcome for LM and LMM is mainly based on single modality patient series from different institutions [6]. Therefore, any comparisons of radiotherapy series to surgical series have to be made with caution, as patients undergoing radiotherapy often have unfavorable characteristics such as large lesions or comorbidities which may result in inferior outcome irrespective of the therapeutic modality [7].
The Australian phase 3 trial RADICAL (NCT02394132) is currently the only ongoing prospective trial on radiotherapy for LM listed on clinicaltrials.gov. The trial investigates the efficacy of radiotherapy versus topical imiquimod as a non-surgical treatment for biopsy-proven LM. The primary endpoint is the proportion of treatment failure 6 months after completion of the treatment. The trial is going to enroll a total of 266 patients, and the study completion date is expected in 2021. The protocol recommends normofractionated RT with single fraction doses of 2 Gy and a total dose of 54–60 Gy as the standard regimen for the definitive treatment of LM. Alternatively, hypofractionated schedules with single fraction doses of up to 4 Gy can be used.
