Modern Radiation Therapy for Primary Cutaneous Lymphomas: Field and Dose Guidelines From the International Lymphoma Radiation Oncology Group

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Modern Radiation Therapy for Primary Cutaneous Lymphomas: Field and Dose Guidelines From the International Lymphoma Radiation Oncology Group Lena Specht, MD, PhD,* Bouthaina Dabaja, MD,y Tim Illidge, MD, PhD,z Lynn D. Wilson, MD,x and Richard T. Hoppe, MDjj, on behalf of the International Lymphoma Radiation Oncology Group *Departments of Oncology and Hematology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; yDivision of Radiation Oncology, Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas; zInstitute of Cancer Sciences, University of Manchester, Manchester Academic Health Sciences Centre, The Christie National Health Service Foundation Trust, Manchester, United Kingdom; xDepartment of Therapeutic Radiology, Yale University School of Medicine, New Haven, Connecticut; and jjDepartment of Radiation Oncology, Stanford University, Stanford, California Received Dec 14, 2014, and in revised form Jan 6, 2015. Accepted for publication Jan 9, 2015.

Primary cutaneous lymphomas are a heterogeneous group of diseases. They often remain localized, and they generally have a more indolent course and a better prognosis than lymphomas in other locations. They are highly radiosensitive, and radiation therapy is an important part of the treatment, either as the sole treatment or as part of a multimodality approach. Radiation therapy of primary cutaneous lymphomas requires the use of special techniques that form the focus of these guidelines. The International Lymphoma Radiation Oncology Group has developed these guidelines after multinational meetings and analysis of available evidence. The guidelines represent an agreed consensus view of the International Lymphoma Radiation Oncology Group steering committee on the use of radiation therapy in primary cutaneous lymphomas in the modern era. Ó 2015 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction The purpose of these guidelines is to provide a consensus position on the modern approach to the delivery of Reprint requests to: Lena Specht, MD, PhD, Department of Oncology, Rigshospitalet, Section 3994, Blegdamsvej 9, 2100 Copenhagen, Denmark. Tel: (þ45) 35453969; E-mail: lena.specht@ regionh.dk

radiation therapy (RT) in the treatment of primary cutaneous lymphomas. The present guidelines represent a consensus viewpoint of the Steering Committee of the International Lymphoma Radiation Oncology Group This project was supported by The Connecticut Sports Foundation and The Global Excellence Program of the Capital Region of Denmark. Confict of interest: none. AcknowledgmentsdThe authors thank Ms. Jessi Shuttleworth for coordinating the ILROG guidelines committee.

Int J Radiation Oncol Biol Phys, Vol. 92, No. 1, pp. 32e39, 2015 0360-3016/Ó 2015 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-ncnd/4.0/). http://dx.doi.org/10.1016/j.ijrobp.2015.01.008

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(ILROG). The guidelines are based on the best available evidence and the experience of ILROG members. Primary cutaneous lymphoma is a distinct type of skin lymphoma with a different clinical presentation and prognosis, requiring a different therapeutic approach, and therefore it must be distinguished from nodal or systemic lymphomas, for which cutaneous involvement is secondary. In lymphoma classification, primary cutaneous lymphomas are included as separate entities. Distinct types of cutaneous T-cell lymphoma and cutaneous B-cell lymphoma can be distinguished (1, 2). In the Western world, cutaneous T-cell lymphomas constitute 75% to 80% of primary cutaneous lymphomas, with mycosis fungoides the most common type, and cutaneous B-cell lymphomas 20% to 25%. In Asia cutaneous T-cell lymphomas other than mycosis fungoides, in particular cutaneous natural killer (NK)/T-cell lymphomas are much more common, whereas cutaneous B-cell lymphomas are much more uncommon. The guidelines address the most common variants of primary cutaneous lymphomas:  Cutaneous T-cell lymphomas, including mycosis fungoides, primary cutaneous anaplastic large-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, primary cutaneous g-d T-cell lymphoma, and primary cutaneous NK/T-cell lymphoma, nasal type.  Cutaneous B-cell lymphomas, including primary cutaneous follicle center lymphoma, primary cutaneous marginal zone lymphoma, and primary cutaneous diffuse large B-cell lymphoma, leg type. Intravascular large Bcell lymphoma may infrequently be present with disease limited to the skin. Because the presentation, staging, natural history, and outcomes of primary cutaneous follicle center lymphoma and primary cutaneous marginal zone lymphoma are in many ways similar, these will be dealt with in the first section. In addition, primary cutaneous anaplastic large-cell lymphoma, although having a different biology being part of the CD30þ lymphoproliferative diseases, is managed similarly and will be included in this section as well. Primary cutaneous diffuse large B-cell lymphoma, leg type, has a more aggressive behavior and will be dealt with separately. The rarer cutaneous T-cell lymphomas, subcutaneous panniculitis-like T-cell lymphoma, primary cutaneous g-d T-cell lymphoma, and primary cutaneous NK/T-cell lymphoma, nasal type, will be briefly mentioned. Finally, mycosis fungoides will be considered separately and in more detail.

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Organization for Research and Treatment of Cancer (EORTC) (3). Local control for primary cutaneous follicle center lymphoma and primary cutaneous marginal zone lymphoma has been well established in multiple retrospective clinical reviews. Local control data for primary cutaneous anaplastic large cell lymphoma are less well established, and a broader spectrum of RT doses has been applied for this histology. Most patients with primary cutaneous follicle center lymphoma (Fig. 1), primary cutaneous marginal zone lymphoma (Fig. 2), or primary cutaneous anaplastic large-cell lymphoma (Fig. 3) who present with T1 disease are served well by local RT. Patients who have T2 disease with a small number of lesions may also benefit from treatment to each individual lesion.

Recommendations  Information before treatment B Expert dermatopathologist review of biopsy. B Staging classification: ISCL/EORTC TNM Classification (3). In general a complete history and physical examination, photography of the skin lesion, laboratory studies including lactate dehydrogenase, and in selected cases serum electrophoresis to exclude a monoclonal gammopathy, are indicated.  Volume B Lesions categorized as T1 (solitary) (T1a <5-cm diameter; T1b 5-cm diameter) are generally treated with “involved lesion RT.” Margins beyond area of clinically evident erythema/induration will vary depending on lesion size and body site and must take into account dosimetry of the beam being used. Margin sizes recommended in the literature range from 0.5 to 5.0 cm (4-8). The EORTC/ISCL recommends a margin of 1.0 to 1.5 cm for primary cutaneous follicle center lymphoma and primary cutaneous marginal zone lymphoma (9), and the ILROG agrees with that recommendation. B The thickness of the lesions must be determined, to ensure adequate coverage also in depth. A margin is

Primary Cutaneous Follicle Center Lymphoma, Primary Cutaneous Marginal Zone Lymphoma, and Primary Cutaneous Anaplastic Large-Cell Lymphoma The staging principles for the non-mycosis fungoides primary cutaneous lymphomas follow the guidelines of the International Society for Cutaneous Lymphomas (ISCL) and the European

Fig. 1. Primary cutaneous follicle center lymphoma presenting as multiple noduli on the left arm.

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Fig. 2. Primary cutaneous marginal zone lymphoma presenting as multiple noduli in the forehead.

added to ensure treatment of microscopic disease in the underlying tissue. The size of this margin is theoretically of the same magnitude as the lateral margins, but it should be modified according to the location of the lesion and the thickness of the soft tissues beneath the lesion. Intact bone and/or fascia are not expected to harbor microscopic disease and may reduce the need for depth coverage. Most lesions can be treated effectively with electrons, usually 6 to 9 MeV (Fig. 4). Generally, bolus will be required to avoid skin sparing. Alternatively, low energy X rays (approximately 100 kV) may be used. For certain situations, for example for deep and bulky tumors or for circumferential lesions, higher-energy photon fields and opposed field treatment (with bolus) may be required to provide adequate coverage.

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 RT dose B Curative RT dose recommendations for primary cutaneous follicle center lymphoma and primary cutaneous marginal zone lymphoma have varied from 20 to 45 Gy, most commonly in the 24- to 40-Gy range (4, 5, 7-10). Local control is excellent within this dose range. Anecdotal examples of local failure have been reported at all dose points. B The EORTC/ISCL recommends a dose range of 20 to 36 Gy for primary cutaneous marginal zone lymphoma and 30 Gy for primary cutaneous follicle center lymphoma (9). The NCCN recommends a dose of 24 to 30 Gy for primary cutaneous marginal zone lymphoma (11), and a similar dose range is often recommended for primary cutaneous follicle center lymphoma, based on the randomized trial of 24 Gy versus 40 Gy for all patients with indolent lymphoma (12). The ILROG recommends 24 to 30 Gy for primary cutaneous follicle center lymphoma and primary cutaneous marginal zone lymphoma. B Palliative doses (2 Gy  2) achieve a complete remission rate of 72%, with 30% of lesions requiring retreatment within a median period of 6.3 months (6). B Dose guidelines for primary cutaneous anaplastic largecell lymphoma are few, with a paucity of reported data from large cases series (13). Doses used have been in the range of 24 to 50 Gy. Additionally, one report recommends a dose of 40 Gy (14). A dose between 24 and 30 Gy can still achieve a durable complete remission, and this is the dose range recommended by the ILROG for primary definitive treatment on the basis of our clinical experience. A multicenter review is in progress and will hopefully clarify the issue.

Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type These are rapidly growing red to bluish tumors often located on the lower extremity (Fig. 5). The term leg type reflects the predominant but not exclusive anatomic location of these tumors. It is seen often in elderly patients (15). In contrast to the indolent cutaneous lymphomas discussed earlier, these lymphomas tend to relapse in extra-cutaneous sites. Solitary or localized disease is treated with R-CHOP (rituximab, cyclophosphamide, adriamycin, vincristine, and prednisone) (16), followed by local RT. If the patient does not tolerate chemotherapy, RT alone or combined with rituximab alone may be used (17).

Recommendations

Fig. 3. Solitary primary cutaneous anaplastic large-cell lymphoma.

 Clinical target volume: Pre-chemotherapy gross tumor volume with margins of 1 to 2 cm.  Technique: Most lesions can be treated effectively with electrons, usually 6 to 9 MeV. Generally, bolus will be required to avoid skin sparing. For certain body surfaces, higher-energy photon fields and opposed-field treatment

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Fig. 4. Electron field for the treatment of a localized cutaneous lymphoma in the skin of the forehead (left). The wire is the skin collimation, the red is the field. An inner eye shield was used to protect the lens of the right eye. Bolus was added on top. The isodose distribution is shown in 2 CT-scan slices (center and right). (with bolus) may be required to provide adequate coverage.

 Dose: 36 to 40 Gy is recommended. If no systemic treatment is given, a dose of 40 Gy is recommended.

Subcutaneous Panniculitis-Like T-Cell Lymphoma Patients with the a/b T-cell phenotype and solitary skin lesions should be treated with RT, usually with electrons. Little information on dose is available, but doses 40 Gy have been used.

Primary Cutaneous g-d T-Cell Lymphoma Patients often present with generalized skin lesions. They respond poorly to systemic treatment. Local control may be achieved with RT to doses of 24 to 30 Gy, but patients tend to relapse.

Primary Cutaneous NK/T-Cell Lymphoma, Nasal Type In patients with localized skin disease, RT is the first choice of treatment. Recommended doses are as for NK/T-cell lymphoma in the upper aerodigestive tract: 50 Gy to the initial lesion and a boost of 5 to 10 Gy to residual disease.

Mycosis Fungoides

Fig. 5. Primary cutaneous large B-cell lymphoma, leg type, presenting as multiple nodules on the right leg. Before treatment (top), after 2 cycles of R-CHOP (rituximab, cyclophosphamide, adriamycin, vincristine, and prednisone) (middle), and 2 months after radiation therapy.

Making a diagnosis of mycosis fungoides is of paramount importance, to distinguish it from benign skin diseases such as parapsoriasis, or a self-limiting disease like lymphomatoid papulomatosis, or an aggressive disease with worse clinical outcome like epidermotropic CD8þ cutaneous Tcell lymphoma. Establishing a robust diagnosis can be difficult, may require multiple biopsies, and always requires clinico-pathologic correlation.

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Fig. 6.

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Mycosis fungoides with widespread patches.

Patients should be staged and stratified according to established prognostic factors (18). Therapy can then be personalized according to the determined approximate survival, patient comorbidities, and preferences. Therapy can vary from skin-directed therapy, local RT, to total skin RT, systemic biologics, or chemotherapy, and in some cases associated with poor prognosis, allogeneic stem cell transplantation may be recommended. Both the folliculotropic variant and large-cell transformation carry an inferior outcome (19-23). When the disease is limited to patches (Fig. 6) and plaques (Fig. 7) with no extra-cutaneous involvement, skin-

Fig. 8. Mycosis fungoides with numerous tumors, before treatment (top) and 6 months after total skin electron beam therapy with boost to thicker lesions (bottom). directed therapy is usually the preferred option. When tumors are present, excellent local control can usually be achieved with RT (Fig. 8). With advanced-stage disease, specifically with Sezary syndrome, systemic biologics, chemotherapy, photopheresis, or allogeneic transplant is indicated. Radiation therapy is a highly effective treatment approach for mycosis fungoides, and local treatment is effective for eradication of uni-lesional disease or palliation of multisite disease. Comprehensive programs of total skin electron beam therapy (TSEBT) may be used for effective palliation, and these patients may often have long-term disease-free intervals (Fig. 9).

Recommendations

Fig. 7.

Mycosis fungoides with numerous plaques.

 RT dose B Local palliation: Although exquisitely radiosensitive, ultralow doses (2 Gy  2) achieve a complete response rate <30%, and higher doses (8 Gy) are recommended, which achieve complete response rates >90% (6). Doses in the range of 8 to 12 Gy allow retreatment. However, tumor stage or large-cell transformation requires higher doses. Although 8 Gy may be given in a single fraction with good results

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Fig. 9. Mycosis fungoides with tumors and plaques, before treatment (left) and 7 years after total skin electron beam therapy (right). (24), fractionation should be determined on the basis of the normal tissue complication probability, considering the irradiated volume, the condition of the skin, prior RT to the site, and whether TSEBT is considered. Often, patients will require reirradiation,

B

and smaller fractions may be preferred. Fraction sizes of 3 to 5 Gy are generally very well tolerated. Uni-lesional mycosis fungoides: Dose range in the few reported series has been 6 to 40 Gy, with local recurrence unusual above 24 Gy (25, 26). A

Fig. 10. Patient positions for total skin electron beam therapy, 6-field technique. The straight anterior, right posterior oblique, and left posterior oblique fields are treated on one day. The straight posterior, right anterior oblique, and left anterior oblique fields are treated the next day.

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reasonable dose range is 24 to 30 Gy. Because the majority of patients respond to lower radiation doses, we encourage the use of doses of 20 to 24 Gy. B Total skin treatment: Considering the dose range 8 to 36 Gy, higher total doses have been associated with higher complete response rates (27). However, complete responses, even in the higher range, often are not durable. Recent attention has been focused on the potential value of lower-dose (10-12 Gy) TSEBT, which has the benefits of being briefer in duration, with fewer side effects, and the opportunity for retreatment if required (28-30).  RT technique B Local palliation: Treatment includes the lesion of interest plus 1.0- to 2.0-cm margins. B Uni-lesional mycosis fungoides: Given the “curative” nature of this treatment, margins 2 cm are generally used (25, 26). B TSEBT: This is technically challenging and requires careful attention to dosimetric technique (31, 32). A variety of techniques may be used to ensure total skin coverage (33), including large electron field techniques (34-36), rotational techniques (37-39), and techniques involving patient or beam movement during irradiation (40, 41). Generally, these require treating patients in the standing position on a rotating platform or else assuming multiple different positions to expose as much as possible all body surfaces. The 6-field large electron field technique developed at Stanford is the most commonly used (36). The 6 positions used for this technique are shown in Figure 10. - “Shadowed” areas, especially if they are involved by mycosis fungoides, require supplemental treatment. This may include the top of the scalp, soles, and perineum, as well as areas under the breasts, beneath a panniculus, etc. - Supplemental boost treatment may be delivered to tumors early during the course of TSEBT, to decrease their thickness and enhance penetration by the TSEBT. - As appropriate for individuals, shielding of the eyes may be with either internal or external shields. The scalp may be shielded selectively.  RT beam quality B Palliation or uni-lesional mycosis fungoides: Generally, treatment with electrons is the beam of choice. Patches are treated effectively with 6-MeV electrons (plus bolus). Plaques may be treated with 6- to 9MeV electrons (plus bolus), but exophytic tumors may require even higher energy electrons, depending on their thickness. Alternatively, low energy X rays may be used (approximately 100 kV). Occasional localizations of disease on extremities or very complex contoured surfaces may require treatment with higher-energy photons (approximately 6 MV) and

International Journal of Radiation Oncology  Biology  Physics

B

multiple field arrangements to ensure homogeneity of dose distribution. TSEBT: Techniques for degrading electron beams to make them suitable for total skin treatment vary. The ultimate goal is to achieve dose homogeneity in the coronal plane, a Dmax at the skin surface (where the dose is prescribed), and an 80% dose at 0.7- to 1.0cm depth.

Conclusion Radiation therapy for primary cutaneous lymphomas is a highly individualized treatment, depending on the histologic type of lymphoma and the location and extent of involvement of the skin. Electron therapy (or even lowenergy X rays) is often indicated, to avoid unnecessary irradiation of deeper structures. Special techniques such as TSEBT may be needed to cover more extensive lesions. The unique histopathologic classification and clinical course of primary cutaneous lymphomas must be taken into account when determining the overall treatment strategy. Radiation therapy to skin lesions plays a major role in the treatment of these lymphomas.

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