
==== Front
Adv Radiat Oncol
Adv Radiat Oncol
Advances in Radiation Oncology
2452-1094
Elsevier

S2452-1094(24)00122-2
10.1016/j.adro.2024.101559
101559
Teaching Case
Taming the Lion: A Report of Pencil Beam Scanning Proton Therapy for Severe Leonine Facies
Lester Scott C. MD Lester.Scott@mayo.edu
a⁎
Johnson Emma F. MD b
Breen William G. MD a
Khurana Arushi MBBS c
a Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota
b Department of Dermatology, Mayo Clinic, Rochester, Minnesota
c Department of Hematology, Mayo Clinic, Rochester, Minnesota
⁎ Corresponding author: Scott Lester, MD Lester.Scott@mayo.edu
29 6 2024
9 2024
29 6 2024
9 9 1015591 2 2024
4 6 2024
© 2024 The Authors
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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pmcCase

The patient is a 70-year-old man with an approximately 2-year history of cutaneous T-cell lymphoma (CTCL) before presenting with leonine facies (LF). At the time of diagnosis, he presented with severe pruritis, erythroderma involving 90% of body surface area, and palpable bilateral inguinal lymph nodes. Skin biopsy at diagnosis revealed an atypical CD4-positive T-cell infiltrate with focal epidermotropism. Large cells, positive for CD30, accounted for approximately 50% of the T-cell infiltrate, consistent with a diagnosis of CTCL with large cell transformation. There were no clonal T-cell populations or sezary cells detected within the blood compartment. The patient was determined to have stage T4N3M0B0 (IVA). Given the presence of large cell transformation, he was treated with multiple lines of systemic therapy, including 6 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone, followed by 3 cycles of romidepsin, and 3 cycles of gemcitabine. The patient continued to progress through these regimens without achieving any sustained response lasting more than 3 months. He was then switched to brentuximab vedotin, a CD30 targeting antibody-drug conjugate (CD30+ staining in 50% of cells), and palliative radiation was administered to the chin at an outside hospital. A total of 800 cGy in 1 fraction was administered using electrons to an area spanning the right side of the lips to the right submandibular area. The lesion in this area experienced a partial transient reduction in volume. He demonstrated persistent progression in the skin with a mixed response in the lymph nodes. At this point, he was referred to our institution.

He subsequently enrolled in a phase 1 clinical trial of nivolumab and duvelisib for advanced-stage mycosis fungoides. Modified Severity-Weighted Assessment Tool (mSWAT) at the initiation of this study was 125.5. He was also admitted to the inpatient dermatology service for continuous wet dressings and whirlpool therapy to palliate severe symptoms, including pruritus and pain, and to address multiple areas of skin breakdown. He had a clear, short-lived palliation of symptoms during and shortly after hospitalization. However, he continued to experience progression, and approximately 1 month after initiating nivolumab/duvelisib, he was switched to bendamustine after receiving 3 doses of high-dose methylprednisolone. Although this change in therapy was rapid, it was felt to be necessary because of the rapid rate of progression and severity of his symptoms. Given the extent of disease, he was also treated with rasburicase for tumor lysis prophylaxis. At this juncture, he formally received a diagnosis of LF. Two days later, he experienced a fall, which was at least in part attributable to bulky disease impairing complete opening of his eyes. Physical examination demonstrated red-to-violet infiltrative papules, plaques, nodules, and tumors involving extremities, trunk, and face with background erythroderma and exfoliation. The infiltrative, crusted, and weeping plaques of the face and ears resulted in exaggeration of normal skin folds consistent with LF (Fig. 1).Figure 1 Severe leonine facies. The patient provided written consent for use of the images contained in this manuscript for scientific publication.

Figure 1

Additionally, he reported weight loss secondary to bulky perioral lesions obstructing his ability to eat. The patient was admitted for intense, around-the-clock skin-directed therapy with topical corticosteroids, wet dressings, and whirlpool therapy. Doxycycline was initiated for superficial impetiginization, and radiation oncology was consulted for palliative radiation.

He underwent repeat biopsy (Fig. 2) and was referred for irradiation. He underwent simulation immediately, and pencil beam scanning proton therapy was started 5 days after admission. A total of 2000 cGy relative biological effectiveness (RBE) was administered in 4 daily fractions (Fig. 3). Setup was performed using a custom 5-point thermoplastic mask and custom neck pillow. The target was the entire skin and superficial soft tissue involved with disease on the face and neck. The lesions in some areas were more than 20 mm thick, which created markedly irregular surface. Underdosing was used around the eyes to minimize the risk of corneal toxicity.Figure 2 Skin biopsy from the left posterior forearm demonstrating an infiltrate of large, pleomorphic, and cytologically atypical lymphocytes within the dermis and with marked epidermotropism (hematoxylin and eosin stain; 200 ×).

Figure 2

Figure 3 Dose wash showing 50% to 110% (1000-2200 cGy relative biological effectiveness [RBE]) of the prescribed radiation dose with sparing of deep structures.

Figure 3

After completion of intensity modulated proton therapy, he transitioned immediately to total skin electron beam therapy delivered as 1200 cGy in 8 daily fractions. A combination of external eye shields and total face shielding was employed to account for the initial proton therapy. At the end of his course, he experienced brisk dermatitis over his scalp and neck and grade 3 perioral mucositis. The entire course of radiation lasted 16 days. Three weeks later, he returned for follow-up, and clinical examination demonstrated a complete response over the face and neck (Fig. 4). He experienced a very good partial response over the rest of his skin, but scattered nodules remained, particularly around the inner thighs. He had resolving mucositis over the lower lip and dry desquamation over the lower posterior neck, likely where the skin received contribution from both the total skin electron beam therapy and proton therapy.Figure 4 Three weeks after radiation, the patient demonstrated a complete clinical response and perioral mucositis.

Figure 4

After this phase of treatment, he slowly returned to independent living. Next-generation sequencing demonstrated an FYN-TRAF3IP2 chromosomal rearrangement, loss of CDKN2A, 2B, microsatellite stability, and tumor mutational burden of 9.5 m/MB. He was subsequently treated with bendamustine and brentuximab for 4 more cycles and achieved a complete clinical response but did eventually progress on brentuximab maintenance for 3 cycles. Further progression was managed by rechallenging with bendamustine without response, followed by 2 cycles of pralatrexate and focal radiation therapy. He continued to experience progression with a declining performance status as the menu for additional systemic therapies dwindled. He passed away 14 months after completing total skin electron beam therapy. Despite the life-ending progression, he remained free of LF, and the only progression above the clavicles had been rare patches and thin plaques (Fig. 5).Figure 5 Twelve months after radiation, the patient demonstrated durable absence of leonine facies with minor patches and thin asymptomatic plaques over the face.

Figure 5

Discussion

Leonine facies can arise from a multitude of conditions including cutaneous T-cell lymphoma. It is an uncommon and aggressive manifestation of CTCL, generally associated with a poor prognosis and other high risk features of disease including Sezary Syndrome.1 While it can occur at the initial diagnosis, it is most commonly encountered as a manifestation of progression after previous therapies. No standard therapy exists specifically for LF and treatment is individualized. Complete remission of LF is rare and survival after diagnosis is quite limited. To the best of our knowledge, proton therapy has not been reported previously in the literature for cutaneous lymphoma of any kind and is only rarely described for other cutaneous conditions. Yet, we believe that in rare circumstances such as LF refractory to systemic therapies, it offers several advantages over other available radiation therapy forms. Previously reported radiation therapy techniques for patients with LF from CTCL have demonstrated remarkably poor efficacy. In the largest report of 10 patients with LF treated with electron beam therapy, complete remission was described in only 1 patient and partial response in 3 patients.2 Thus, there is clearly a need for improved radiation therapeutic and non-radiation therapeutic options for this condition.

The first advantage of proton therapy is that no material needs to be fixed to the patient to facilitate superficial radiation. Low-energy electrons or megavoltage photons produced by commercially available linear accelerators are innately skin-sparing. To achieve coverage of the superficial areas, placement of material (typically referred to as bolus) is required to bring the dose to the skin surface. In the case of our patient, fixing bolus material over the nares and mouth where disease was prevalent would have obstructed his airway. Additionally, it can be challenging to fix material to areas that are painful to touch, actively weeping or oozing, or sloughing. Third, our technique eliminates the need for fabricating complex bolus using 3-dimensional printing or other advanced techniques, which are often needed to minimize air gaps. With proton therapy, a range shifter is affixed to the head of the machine to facilitate targeting of superficial tissues. The second advantage is that spot-scanning technology enables precise carving of the dose around the eyes without the need for use of internal eye shields. It is unlikely that shields for electron therapy could have been placed in this patient, given the bulk of his disease and risk of corneal injuries with aggressive placement. The third advantage is that multifield feathering is straightforward, using multifield optimization with intensity modulated proton therapy. This enables use of multiple interdependent beam angles to cover a complex shape without the uncertainties introduced by abutting electron fields. Lastly, the confluence of bulky lesions created a highly heterogeneous array of varying depths. A radiation modality was needed to span this depth while also sparing deeper radiosensitive structures such as the brain, cochleas, retinas, pharyngeal mucosa, salivary glands, and tongue. Megavoltage x-rays could achieve the needed depth but would increase the dose to the uninvolved organs. Electron therapy lacks intensity modulation, performs poorly for irregular shapes and variable depths, and field matching would be limiting.

A short (hypofractionated) radiation course was chosen for the patient for multiple reasons. Technically, proton therapy is very sensitive to changes in anatomic shape and size. Completing therapy quickly minimized the risk of disease shrinkage and/or swelling during radiation that could detrimentally impact plan quality, alter the thermoplastic mask fit, or require a replan with a treatment delay. Additionally, the patient was in a vulnerable state with declining nutritional intake, and a shorter regimen was felt to be more achievable, particularly when considering that the table time for complex proton therapy fractions can exceed 1 hour. A total of 2000 cGy (RBE) in 4 fractions is an aggressive dose for cutaneous T-cell lymphoma. This was chosen because the disease was causing life-threatening complications, and LF has been reported to have a low complete response rate. Given these conditions, an aggressive regimen was pragmatically determined to maximize the chance for successful salvage. Fortunately, insurance coverage was promptly obtained, but we acknowledge that this could be a limiting step in similar circumstances. The patient did experience grade 3 perioral mucositis, which we attribute primarily to the use of aggressive hypofractionation, but the recent exposure to system therapy and prior overlapping radiation therapy may have contributed. Although we cannot draw any conclusions from comparing this case report, our treatment used 20 Gy (RBE) in 4 fractions, which is biologically intensified compared with the previously noted series, which most commonly reported 12 Gy. Thus, the excellent response here may be a consequence of the higher dose used.

LF is a challenging and sometimes life-threatening manifestation of CTCL. A multidisciplinary approach of cutaneous lymphoma management with experts in dermatology, hematology, and radiation oncology is essential. Intensity modulated proton therapy has multiple advantages for treatment of patients with LF, and when radiation therapy is indicated, it should be considered in this rare circumstance.

Disclosures

Scott C Lester; royalties from Empyrean Medical Systems.

Sources of support: None.
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References

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2 Brown DN Wieser I Wang C Dabaja BS Duvic M. Leonine facies (LF) and mycosis fungoides (MF): A single-center study and systematic review of the literature J Am Acad Dermatol 73 2015 976 986 26476898
