Radiation therapy is an extraordinarily effective skin-directed therapy for cutaneous T-cell lymphomas. Lymphocytes are extremely sensitive to radiation and a complete response is generally achieved even with low doses. Radiation therapy has several important roles in the management of mycosis fungoides. For the rare patient with unilesional disease, radiation therapy alone is potentially curative. For patients with more advanced cutaneous disease, radiation therapy to local lesions or to the entire skin can effectively palliate symptomatic disease and provide local disease control. Compared with other skin-directed therapies, radiation therapy is particularly advantageous because it can effectively penetrate and treat thicker plaques and tumors.
Key points
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Radiation therapy is one of the most effective treatment modalities in cutaneous T-cell lymphomas.
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Local radiation therapy is potentially curative in unilesional mycosis fungoides.
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Local radiation therapy can effectively palliate symptomatic lesions in patients with cutaneous T-cell lymphoma.
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Total skin electron beam therapy should be used in patients with diffuse mycosis fungoides unresponsive to other modalities or when thick plaques or tumors are present.
Introduction
Cutaneous T-cell lymphomas (CTCLs) are comprised of several histologic subtypes of non-Hodgkin lymphoma characterized by localization of malignant lymphocytes to the skin. Mycosis fungoides (MF) is the most common type of CTCL, accounting for 54% of CTCL diagnoses from 2001 to 2005 in one Surveillance, Epidemiology, and End Results registry review. Other subtypes of CTCL include cutaneous CD30 + T-cell lymphoproliferative disorders and primary cutaneous peripheral T-cell lymphomas.
Radiation therapy (RT) is one of the most effective treatment modalities for CTCL. Lymphocytes are among the most radiosensitive of all cells. Low doses of radiation yield impressive local responses with minimal side effects. For patients with MF, RT has several different clinical applications. For the rare patient with unilesional disease, RT alone is potentially curative. For patients with more advanced cutaneous disease, RT to local lesions or to the entire skin can effectively palliate symptomatic disease and provide local disease control. Finally, symptomatic nodal or visceral disease can also be palliated with RT if necessary. This article reviews basic information regarding the administration of RT and reviews the published literature supporting the use of such for MF and primary cutaneous anaplastic large cell lymphoma (cALCL). Cutaneous peripheral T-cell lymphomas are rare and are not discussed further.
Introduction
Cutaneous T-cell lymphomas (CTCLs) are comprised of several histologic subtypes of non-Hodgkin lymphoma characterized by localization of malignant lymphocytes to the skin. Mycosis fungoides (MF) is the most common type of CTCL, accounting for 54% of CTCL diagnoses from 2001 to 2005 in one Surveillance, Epidemiology, and End Results registry review. Other subtypes of CTCL include cutaneous CD30 + T-cell lymphoproliferative disorders and primary cutaneous peripheral T-cell lymphomas.
Radiation therapy (RT) is one of the most effective treatment modalities for CTCL. Lymphocytes are among the most radiosensitive of all cells. Low doses of radiation yield impressive local responses with minimal side effects. For patients with MF, RT has several different clinical applications. For the rare patient with unilesional disease, RT alone is potentially curative. For patients with more advanced cutaneous disease, RT to local lesions or to the entire skin can effectively palliate symptomatic disease and provide local disease control. Finally, symptomatic nodal or visceral disease can also be palliated with RT if necessary. This article reviews basic information regarding the administration of RT and reviews the published literature supporting the use of such for MF and primary cutaneous anaplastic large cell lymphoma (cALCL). Cutaneous peripheral T-cell lymphomas are rare and are not discussed further.
Mycosis fungoides
Local Radiation Therapy
In rare circumstances, MF presents as a solitary lesion, or small number of clustered lesions, that are amenable to a definitive course of therapy where the goal of treatment is long-term disease control. More commonly, patients with MF have more diffuse presentations where symptom palliation and local disease control are the fundamental goal of treatment. In circumstances where other modalities are not effective or a rapid response is desired, local RT can be efficacious. These circumstances include cosmetically disfiguring lesions on the face; tumors and thick plaques where radiation can effectively treat to the necessary depth; and lesions that are painful, pruritic, or weeping.
Clinical applications of local radiation therapy
Minimal stage IA disease
Patients with patches or plaques covering less than 10% of the body surface area without significant blood, nodal, or visceral involvement have clinical stage IA MF. These patients have a favorable prognosis with survival similar to age-matched control subjects without MF. In a retrospective cohort analysis including 121 patients with clinical stage IA disease, the median survival had not been reached after more than 32 years of follow-up. Three (2%) of 122 patients had died of MF during the study period.
The subgroup of patients with “minimal” stage IA MF (ie, unilesional or up to three close lesions) have an especially favorable prognosis. Patients with this disease may experience long-term remission or ostensibly even “cure” with local RT alone. Several small studies have reported outcomes of local RT in minimal stage IA disease. Results of these studies are summarized in Table 1 . Wilson and colleagues evaluated 21 patients with minimal disease treated with local RT. Thirteen patients had unilesional MF. The complete response (CR) rate to localized RT was 97%. Disease-free survival (DFS) for the entire group at 5 and 10 years was 75% and 64%, respectively. Improved DFS at 10 years was reported in patients with unilesional disease (85%) and those receiving doses of at least 20 Gy (91%).
| Study (Ref) | Extent of Disease | No. of Patients | No. of Sites | RT Dose (Median) | CR Rate | Relapse in RT Field | DFS 5 y | DFS 10 y |
|---|---|---|---|---|---|---|---|---|
| Wilson et al, 1998 | 1–3 lesions | 21 | 32 | 20 Gy | 97% | 3/31 | 75% | 64% |
| Micaily et al, 1998 | 1 lesions | 18 | 18 | 30.6 Gy | 100% | 0/18 | NR | 86% |
| Piccinno et al, 2009 | 1–4 lesions | 15 | 22 | 22 Gy | 95% | 4/22 | 51% | 51% |
Micaily and colleagues reported on the outcomes of 18 patients with unilesional stage IA MF. This represented only 5% (18 of 325) of patients with MF treated at the study institution. Most patients received 30.6 Gy of local RT. The CR rate was 100%. Relapse-free survival (RFS) and overall survival at 10 years was 86% and 100%, respectively. Two relapses occurred, both confined to the skin at distant sites and subsequently treated with topical nitrogen mustard.
Finally, Piccinno and colleagues evaluated 15 patients with minimal stage MF treated with a median dose of 22 Gy. Complete remission of treated lesions was observed in 95% with the other 5% achieving a partial remission. At 5 and 10 years the overall relapse-free rate was 51%.
In summary, less than 5% of patients present with minimal stage IA MF. This unique subgroup may be managed effectively with local RT alone. Available studies report excellent responses to local RT with 95% to 100% of lesions experiencing a CR. Many patients have a prolonged disease-free interval with the best outcomes seeming to be with RT doses of 20 to 30 Gy.
Palliation of individual lesions
Local RT is an effective palliative therapy for patients with all stages of MF with symptomatic cutaneous lesions. Local RT is often used to treat MF lesions refractory to other skin-directed or systemic therapies. Several retrospective studies have demonstrated very high rates of CR (>95%) of individual MF lesions with fractionated courses of RT. A dose–response relationship has emerged with higher doses being associated with higher rates of CR and local control. Cotter and colleagues evaluated the impact of radiation dose on local control in 111 MF lesions (53% plaques, 47% tumors). They demonstrated a CR to treatment in all lesions receiving greater than 20 Gy. Local recurrence was inversely associated with dose. The rate of local in-field recurrence was 42% with doses less than or equal to 10 Gy, 32% for doses 10 to 20 Gy, 21% for doses 20 to 30 Gy, and 0% when the dose was greater than 30 Gy. There was no difference in response rates between plaques and tumors. It was suggested that tumor doses equivalent to 30 Gy at 2 Gy per fraction were required for adequate control of MF lesions.
Palliation of individual skin lesions with very short courses of RT has also been reported. Short courses of radiation are more convenient for patients and are potentially more cost effective compared with multiple fractions. Thomas and colleagues reported their experience treating 270 CTCL lesions (primarily MF) with a single fraction of local RT. Of the 58 patients included in the study, 21 (36%) had patch/plaque disease, 34 (59%) had tumor-stage disease, and 3 (5%) had erythroderma only. Most patients (97%) were treated with a single dose of greater than or equal to 7 Gy. A CR was observed in 94% of lesions and the rate of relapse in the radiation field was 1% with a median follow-up of 41.8 months. Large-cell transformation and tumor morphology were associated with a lower CR rate. Neelis and colleagues reported a CR rate of 92% when patients with MF were treated to a total dose of 8 Gy in two fractions. Local relapse occurred in 8% of treated sites. Of note, only 30% of lesions treated with 4 Gy in two fractions achieved a CR. Patients who either did not have a CR or failed locally were retreated with 20 Gy in eight fractions without complication. No significant acute or long-term toxicities were reported in either study.
In summary, local RT is very effective in the palliation of MF skin lesions. Short courses of one to two fractions (7–8 Gy) have yielded favorable results and can be used for patients requiring rapid palliation or who would have a difficult time coming in for a more conventional regimen. Generally, smaller lesions are optimally suited for a single fraction of treatment, whereas larger lesions are often better managed with a more protracted fractionated approach.
Palliation of nodal and visceral disease
Most patients with MF never develop symptomatic nodal or visceral disease. However, just as with other malignancies, local RT can be used in this setting for symptom palliation. Patients with advanced-stage MF may experience pain, swelling, or other local symptoms secondary to bulky lymphadenopathy. Visceral metastatic disease can impact the function of an involved organ. RT in these circumstances is typically performed with computed tomography (CT)–based three-dimensional planning with megavoltage photon RT. Typical doses used in our institution range from 20 to 30 Gy using 2- to 3-Gy fractions.
Side effects
Acute and long-term side effects of local RT directed at skin lesions are minimal. Patients may develop erythema and occasionally dry or moist desquamation within the treatment field. Ulcerated lesions sometimes appear worse shortly after starting RT. The skin generally heals rapidly after a course of radiation. Nothing more than topical symptom management is typically necessary during treatment. In the long-term patients may have pigmentation changes and alopecia in the treated areas. There is a theoretic risk of secondary cutaneous malignancies, although reports of this in the literature are rare.
Technique and administration
Local RT is typically delivered by means of a linear accelerator ( Fig. 1 ). Most linear accelerators can produce high-energy photon (x-rays) and electron beams. Both photons and electrons can be used depending on the clinical circumstances. Electrons have unique properties that make them particularly suited to treating cutaneous lesions. Electron beam therapy delivers dose close to the skin surface after which the dose falls off extremely rapidly, limiting radiation exposure to deeper tissues. Increasing electron energies can be chosen to treat deeper lesions. The association between the depth dose and electron energy is plotted in Fig. 2 .
Most electron beam treatments for superficial skin lesions are planned clinically rather than with imaging modalities, such as CT or MRI ( Fig. 3 ). The radiation oncologist delineates a margin of 1- to 2-cm around visible and/or palpable disease. A lead cutout is then created conforming to the shape of the target. The lead cutout is inserted into the treatment machine thus focusing the radiation beam to the desired shape. As electrons begin depositing their dose on contact with the skin, there can be some degree of “skin sparing” with electron beam therapy (see Fig. 2 ). To address this phenomenon, material referred to as bolus is placed over skin lesions before treatment. Bolus is a tissue-equivalent material that starts the process of dose deposition allowing the maximum dose to be at the skin surface. The radiation dose is often fractionated, or divided into multiple smaller doses. Patients are treated daily excluding weekends until their course is completed. Each treatment, including time for set-up, lasts approximately 15 minutes.
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