Isaac Brownell, MD, PhD
Dermatology Service
Nancy Lee, MD, and
Alice Ho, MD, MBA
Department of Radiation Oncology
Memorial Sloan-Kettering Cancer Center
New York, NY

Cutaneous melanoma is a lethal malignancy that remains a therapeutic challenge despite an expanding number of advanced treatment options.¹ The only highly effective therapy is early detection and complete surgical excision of local disease. In patients presenting with more advanced melanoma, surgery can be combined with systemic therapies and/or radiation.²

Radiotherapy in the treatment of melanoma is likely underutilized owing to a historic misperception that all melanomas are radioresistant.³ More recent work suggests that melanomas show a range of sensitivity to radiation, and growing evidence supports use of this modality in select patients.^4,5

Radiation Therapy

Radiotherapy utilizes ionizing radiation to damage DNA and subsequently arrest cancer cell growth. When treating internal targets with radiotherapy, high-energy X-rays in the megavoltage range (4–16 MV) are typically used. In treating primary, recurrent, or metastatic disease in the skin, it is possible to use superficial radiotherapy to minimize collateral tissue damage and increase the therapeutic index. Superficial radiotherapy uses lower-energy superficial or orthovoltage X-rays (10–500 kV) or electron beams, as these forms of radiation have limited tissue penetration. With superficial radiotherapy, the majority of the energy is deposited within a shallow treatment volume near the body’s surface, and underlying structures are spared. In particular, electrons allow rapid dose fall-off beyond skin depth, thereby limiting the amount of radiation delivered to deeper structures. In the past, Grenz ray machines were used as a source of superficial “soft X-radiation”;¹¹ however, they are now virtually non-existent in the US.

Use of superficial radiotherapy is limited, in part, by its effect on adjacent normal tissues. Typically, radiosensitive tumor cells exhibit a steep dose-response curve compared to normal cells, which can recover from small doses of radiation. This difference allows for the use of fractionated radiotherapy, where the total therapeutic dose of radiation needed to treat the tumor is divided into multiple, small, “conventional” dose fractions administered over time. Conventionally fractionated radiotherapy has less impact on surrounding normal tissues and is better tolerated than low-fraction, high-dose (“hypofractionated”) regimens.

Melanoma and Radiotherapy

Unlike highly radiosensitive tumors, melanomas often have a dose response to radiation that is similar to late-responding normal tissues. Because melanoma cells may effectively recover from the damage caused by conventional-fractionation radiation doses, higher doses per treatment may be needed to achieve cytotoxicity. Therefore, hypofractionated dosing regimens are often selected. Most treatment centers opt for hypofractionated regimens that are effective in controlling melanoma yet relatively well tolerated. There is still debate in the field regarding the potential efficacy of conventional-fraction radiotherapy,⁶ and further studies are needed to explore this issue.

The National Comprehensive Cancer Network (NCCN) guidelines on melanoma treatment support the use of radiation for palliation of disseminated inoperable disease and also as an alternative treatment for unresectable in-transit metastases in local dermal lymphatics.⁷ While radiation is becoming more common in the treatment of isolated or limited (oligometastatic) internal organ disease, it is infrequently the treatment of choice for in-transit metastases.

In addition to the NCCN indications, several retrospective series demonstrate the efficacy of adjuvant radiotherapy to regional lymph node basins in select patients at high risk for regional recurrence.^4,6,8 This application is often limited to patients with high-risk clinical and pathologic features, as the increased local control must be balanced against the risks of complications such as lymphedema or fibrosis, and the fact that overall survival is probably not improved. Radiation, along with systemic therapies, is also a second-line consideration for the treatment or palliation of any melanoma where surgery is not feasible. For inoperable cutaneous lesions, superficial radiation is a potential therapeutic option.

Superficial Radiation for Select Melanomas

Only in exceptional circumstances is a surgical treatment approach impossible and thus replaced by superficial radiotherapy as the primary treatment for cutaneous melanoma (Table 1). There are also situations where postoperative superficial radiation can be considered (Table 2). In evaluating a patient for radiation, the treatment volume, dosage, and fractionation scheme should be tailored to the individual’s tumor properties, predicted recurrence risk, and surrounding anatomy. Potential late adverse effects such as fibrosis, chronic radiation dermatitis, and radiation-induced carcinomas should also be considered. Prior radiation exposure is also a consideration, as reirradiation is often poorly tolerated.

Radiation for Lentigo Maligna and Lentigo Maligna Melanoma: Superficial radiotherapy is a second-line treatment option for lentigo maligna (LM). LM is an intraepidermal proliferation of malignant melanocytes that presents as a slowly enlarging pigmented macule, often on chronically sun-damaged skin in elderly patients. When a focus of the tumor invades the dermis, the lesion is called a lentigo maligna melanoma (LMM). LM and LMM are often large and have a predilection for the head and neck. Complete surgical excision of such lesions can require extensive reconstruction, impairing the function of facial structures. In elderly patients unable to tolerate large surgical procedures, or in lesions where the anticipated reconstruction would have notable functional and cosmetic impact, superficial radiotherapy can be considered as primary treatment. Other non-excisional treatment alternatives to consider for unresectable LM include cryotherapy and immunotherapy with topical imiquimod cream.

Retrospective studies suggest that local recurrence rates for LM or LMM treated by superficial radiotherapy compare favorably to surgical treatment approaches,^9,10 but no controlled prospective trials have been conducted. Anecdotally and in our experience, the treatment is tolerated well, shows low morbidity, and results in acceptable cosmetic outcomes. However, there is insufficient evidence to gauge its ultimate impact on rates of disseminated disease, overall survival, or comparative cosmetic outcomes.

Similar to LM, other subtypes of cutaneous melanoma may present in clinical contexts where surgery is impossible or inadvisable. These patients may also be considered for superficial radiotherapy.

When treating a cutaneous melanoma with radiation, the treatment field includes the area of the lesion plus a margin of clinically uninvolved skin. The appropriate size of the safety margin for radiotherapy of melanoma is debatable. For LM, some authors recommend a margin of at least 1 cm,⁹ as they have observed recurrences at the edge of the radiotherapy field when less than 1 cm was used. When planning radiation treatments for pigmented lesions, especially LM, the lesion can be examined with a Wood’s lamp to better delineate the clinical border. If there are questions about the extent of involvement, scouting skin biopsies can be considered to better define the lesion margins. Histological depth of the tumor should guide treatment depth. In LM, involvement of adnexal structures such as hair follicles would warrant a deeper treatment volume. When defining the extent of the disease, photographic documentation and close communication between the dermatologist, dermatopathologist and radiation oncologist can help in designing the optimal treatment volume.

Radiation for In-Transit Metastases: Another potential use of superficial radiotherapy for primary treatment is in controlling in-transit melanoma metastases. The first-line treatment for isolated or limited numbers of local cutaneous metastases is complete surgical excision. But when the lesions are too extensive to excise, alternative approaches such as intralesional chemotherapy or superficial radiation can be considered. While radiation will occasionally control in-transit metastases, the primary goal for this therapy is palliation of fungating or bleeding cutaneous lesions. If the cutaneous metastases are anatomically restricted to a limb, hyperthermic isolated limb perfusion or infusion should also be considered as an alternative treatment approach.

Postsurgical Radiation: Superficial radiotherapy may also have a benefit as an adjuvant therapy to surgery in select cutaneous melanomas. Just as systemic adjuvant therapy should be considered for patients with cutaneous melanoma at high risk for distant metastases, postoperative radiation can be considered for locally advanced disease with features that portend increased locoregional recurrence risk. A number of disease characteristics have been associated with increased local recurrence rates, and have been suggested as relative indications for postoperative superficial radiation (Table 2).^3,4 These include excisions with close or positive margins where further surgery is not possible, head and neck location, mucosal melanoma, recurrent disease, thickness > 4mm, neurotropic or desmoplastic histopathology, ulceration, and satellitosis. Whenever possible in patients with unresectable LMM, the areas of invasion should be identified and surgically excised prior to treating the residual macular lesion with radiation or another alternative modality.

Some non-controlled case series suggest postoperative radiotherapy can reduce rates of local recurrence in high-risk melanoma lesions.^3-5 There is no convincing evidence that this treatment significantly reduces distant metastases or increases overall survival rates. It is important to note that not every patient with one of the aforementioned high-risk features will benefit from radiotherapy, and the potential benefit must be weighed against the potential risks. The epidermis and hair follicles are highly proliferative and are therefore sensitive to radiation. Thus, acute erosive radiation dermatitis and permanent alopecia often accompany superficial radiotherapy. Moreover, the patients are subjected to the time and cost associated with multiple treatments, although these inconveniences are reduced with hypofractionated radiation regimens. Late adverse effects such as atrophy, fibrosis, and ulceration are minimized due to limited dermal penetration of superficial radiation. However, even superficially irradiated patients are at increased long-term risk of developing non-melanoma skin cancers within the treatment field. Monitoring the treatment area for disease recurrence and new malignancies is an important part of the regular ongoing skin surveillance in melanoma patients who receive radiation.

Conclusions

It is now well accepted that deep-penetrating megavoltage radiation therapy has a role in the palliation of metastatic melanoma, especially in treating isolated brain lesions.^4,7 A growing body of evidence also suggests that superficial radiotherapy is effective at improving locoregional control for unresectable LM and as a postsurgical adjuvant in locally advanced disease. Superficial radiation produces favorable cosmetic outcomes and few long-term adverse events. While this treatment modality has great promise, and while there is evidence to suggest that superficial radiotherapy is a reasonable alternative to surgery for LM or LMM,^9,10 no randomized trials have evaluated its efficacy or risks in the treatment of cutaneous melanoma. Controlled, prospective multicenter studies are needed to standardize treatment protocols, identify patient populations that would most benefit, and evaluate the impact on disease-free and overall survival as well as cosmesis.

References