|Year : 2019 | Volume
| Issue : 3 | Page : 117-122
Analysis of the treatment results of localized conventional radiotherapy for early- and advanced-stage cutaneous T-cell lymphoma refractory to other skin-directed therapies
Jaehyeon Park1, Jong-Hun Kim2, Jin Park3, Sun Young Lee1
1 Department of Radiation Oncology, Chonbuk National University Hospital-Chonbuk National University Medical School, Jeonju, Jeonbuk; Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital, Republic of Korea
2 Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital; Division of Cardiovascular-Thoracic Surgery Chonbuk National University Hospital-Chonbuk National University Medical School, Jeonju, Republic of Korea
3 Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital; Department of Dermatology, Chonbuk National University Hospital-Chonbuk National University Medical School, Jeonju, Jeonbuk, Republic of Korea
|Date of Submission||28-May-2018|
|Date of Acceptance||28-Oct-2018|
|Date of Web Publication||26-Sep-2019|
Dr. Sun Young Lee
Department of Radiation Oncology, Chonbuk National University Hospital-Chonbuk National University Medical School, 20, Geonji-ro, Deokjin-gu, Jeonju-si, Jeollabuk-do 561-712
Republic of Korea
Source of Support: None, Conflict of Interest: None
Background: Radiotherapy treatment was used as a skin-directed therapy for early- and advanced-stage cutaneous T-cell lymphoma (CTCL) refractory to other skin-directed or systemic therapies. Materials and Methods: From January 1990 to January 2017, eight patients with CTCL were treated with local radiation therapy. The median age of these patients was 41 years, and the female-to-male ratio was 1:3. The average disease course was 9.2 years. The patients were classified as Stage Ia (three patients), Ib (one patient), IIb (three patients), and III (one patient). Five patients received electron radiotherapy, and three patients received electron and photon radiotherapy. The mean number of treated lesions was 5.2 (range, 2–14 lesions). A median dose of 46 Gy (range, 40–50 Gy) was used. Results: After radiotherapy, complete and partial remission of the irradiated lesion was observed in 81% and 19% of all treated lesions, respectively. The treatment response in the early stage of disease was statistically significant (P = 0.0427). Local relapse was observed in eight lesions (two lesions in the irradiation field and six lesions outside of the irradiation field) after complete remission. A significantly lower recurrence rate was observed in the early stages of the disease (P = 0.0373). Radiotherapy resulted in long-lasting remission with early-stage CTCL. In addition, radiotherapy helped manage symptoms (pain, itching, and hyperkeratosis) in patients with advanced-stage disease. Conclusion: Localized conventional radiotherapy is effective for the treatment of early- and advanced-stage CTCL that is refractory to other skin-directed or systemic therapies, and the treatment is not associated with severe complications.
Keywords: Combination treatment, cutaneous T-cell lymphoma, localized conventional radiotherapy, treatment outcome
|How to cite this article:|
Park J, Kim JH, Park J, Lee SY. Analysis of the treatment results of localized conventional radiotherapy for early- and advanced-stage cutaneous T-cell lymphoma refractory to other skin-directed therapies. Dermatol Sin 2019;37:117-22
|How to cite this URL:|
Park J, Kim JH, Park J, Lee SY. Analysis of the treatment results of localized conventional radiotherapy for early- and advanced-stage cutaneous T-cell lymphoma refractory to other skin-directed therapies. Dermatol Sin [serial online] 2019 [cited 2019 Oct 16];37:117-22. Available from: http://www.dermsinica.org/text.asp?2019/37/3/117/267887
| Introduction|| |
Cutaneous T-cell lymphoma (CTCL) is rare and usually affects people between the ages of 40 and 60 years., CTCL is caused by the uncontrolled proliferation of T-cells in the skin. CTCL is more common in men than in women. The cause of CTCL is unknown,,, and common locations include the lower abdomen, buttocks, upper thighs, and back.,, The symptoms of CTCL depend on the stage of the disease. In early stages, CTCL can look much like eczema or psoriasis with red, rash-like patches on the skin, which may be raised plaques; itching is a common symptom., In advanced stages of the disease, large areas of the skin are affected. The skin is very red, scaly, and itchy and may also be painful. The lesions are often swollen and look thicker in some areas., In early-stage CTCL, the skin is usually treated directly with steroid creams, topical chemotherapy, psoralen and ultraviolet A (PUVA), or radiotherapy.,,, In advanced CTCL or in nonresponders to initial therapy, systemic treatments, such as interferon gamma or interferon alpha, pentostatin, retinoids, fludarabine, acyclovir, 2-chlorodeoxyadenosine, and methotrexate, are used.,,, In addition, radiotherapy is used for skin-directed therapy in CTCL, either as total skin electron beam irradiation (TSEBI) or as a localized treatment with conventional electrons or photons. Because of the radiosensitivity of neoplastic T-cells, TSEBI was developed as an effective modality to treat CTCL. However, the complications of TSEBI are sometimes severe, and patients treated with TSEBI often experience recurrence, particularly those with advanced-stage disease. In recent years, localized conventional radiotherapy, which is recommended for the treatment of single lesions, in early or advanced stages of CTCL, has been proven effective as both a curative and a palliative treatment method. For patients with advanced-stage disease, in particular, radiotherapy alleviates symptoms and delays progression. In this study, we evaluated the results of localized, conventional radiotherapy in eight patients with early and advanced stages of CTCL that is refractory to other skin-directed or systemic therapies.
| Materials and Methods|| |
From January 1990 to January 2017, eight patients with CTCL were treated with local radiation therapy. There were two female and six male patients, ranging from 17 to 89 years of age (median, 41 years). All patients were staged according to the American Joint Committee on Cancer, Ed sixth staging system., The patients were classified as Stage Ia (three patients), Ib (one patient), IIb (three patients), and III (one patient). The mean number of lesions treated was 5.2 (range, 2–14 lesions). All patients underwent a physical examination of the entire skin surface area and a palpation of the lymph nodes, as well as a histological examination and immunophenotyping of the lesions. For the evaluation of metastatic lesions, patients underwent a computed tomography or positron emission tomography scan of the abdomen and pelvis as well as a bone marrow biopsy before staging. Before radiotherapy, all patients received initial treatments, such as topical steroids, PUVA, interferon, or systemic chemotherapy [Table 1], but skin-directed therapies or systemic therapies had failed. Therefore, the patients in this study underwent lesional radiation therapy. Our study protocol was approved by the Institutional Review Board of Chonbuk National University Hospital (IRB No. CUH 2014-05-023).
|Table 1: Characteristics of eight patients with cutaneous T-cell lymphoma|
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Five patients received electron beam radiotherapy, and three patients received a combination of electron and photon beam radiotherapy. The Stage IIIb patient underwent local radiotherapy due to limitations of the treatment machine and the patient's refusal of TSEBI. The total treatment dose ranged from 40 to 50 Gy (median dose, 46 Gy), and it was administered with a fractionated daily dose of 2 Gy/5 days/week.
Radiation therapy was used with a 6 MeV ~ 12 MeV electron beam and a 6 MV photon beam (Varian, Palo Alto, Ca, USA) depending on the characteristics of the lesions. To ensure the application of an adequate radiation dose to the skin surface, a 0.5-cm or 1-cm thick silicon bolus, based on the lesion characteristics, was placed on the disease lesion as a tissue compensator. The electron and photon beams were irradiated in the normal skin area at a distance of 1.5–2 cm from the margin of the lesions. The surrounding normal tissue was shielded with lead (equivalent to 6 mm of Pb). Radiotherapy planned that the 80% isodose line extended 0.7–1.0 cm below the skin surface. Four patients received radiotherapy with adjuvant therapy (PUVA or IFN-a) [Table 2].
|Table 2: Conventional radiotherapy of eight patients with cutaneous T-cell lymphoma (42 treated lesions)|
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The response assessment was conducted 1–2 months after the end of radiotherapy. A complete response (CR) was defined as complete remission of the disease lesions in the radiation field; a partial response (PR) was defined as a regression of >50% and <75% of the lesions in the radiation field; and no response was defined as a regression of <50% of the disease lesions or as a stable or progressive lesion. Treatment response assessments were classified according to the WHO guidelines. The treatment outcomes were analyzed with a Chi-square test (Fisher's exact test), and significance was considered at a level of P < 0.05 using SAS version 9.2 (Cary, North Carolina, USA). Survival was analyzed with Kaplan–Meier survival analysis.
| Results|| |
The mean follow-up period was 50 months (range, 11–133 months). Complete remission of the irradiated lesion (n = 34) was observed in 81% of the total treated lesions (n = 42), and partial remission (n = 8) was observed in 19% of the total treated lesions (n = 42) after radiotherapy [Table 3]. A CR was observed in 13 lesions of early-stage CTCL (Stage Ia and Ib), and 21 lesions were observed in advanced-stage disease (Stage II and III). A PR was not observed for the early lesions, and eight lesions were observed at the advanced stage. The CR rate was statistically significant for early lesions (P = 0.0427). Local relapse was observed in eight lesions (two lesions in the irradiation field and six lesions outside of the irradiation field) after complete remission. Early-stage patients did not have recurrence. Recurrence was diagnosed, on average, 5 months (range, 3–7 months) after the end of radiation treatment. Recurrence was not observed within the field of radiation therapy or outside of the field in the early stage. In the advanced stage, two lesions were found in the field of the radiotherapy range, and six lesions were found outside of the field of radiation therapy (total, eight lesions). The recurrence rate was also significantly lower in the early stages of the disease (P = 0.0373). There were no significant associations between response to treatment and the recurrence of the lesion with gender, age, characteristics of immunohistochemistry, history of previous treatment, total treatment dose, or amount of energy applied during treatment. In early-stage CTCL in particular, radiotherapy was associated with a longer remission. A hyperpigmented keratotic scale was observed on the left anterior thigh of one patient [Figure 1]a, and it disappeared after radiotherapy [Figure 1]b. In addition, pain, itching, and hyperkeratosis were controlled in patients with advanced-stage disease (IIIb). Before treatment, one patient experienced severe pain, itching, eczema, hyperkeratosis, and bleeding in the left ear [Figure 2]a. After radiotherapy, the ear lesion completely disappeared, and a posttreatment biopsy examination confirmed the absence of the previously present lymphoid infiltration. The patient was free of disease in the ear at the most recent follow-up [Figure 2]b. The follow-up periods were 11–132 months (mean, 48 months). Survival was analyzed with Kaplan–Meier survival analysis. The 5-year overall survival rate was 66.7% [Figure 3]a, and the 5-year disease-free survival rate was 62.5% [Figure 3]b. At the most recent follow-up, five patients were alive with no evidence of disease, two patients were alive with evidence of disease, and one patient had died. Acute side effects, including mild dryness at the treatment site of the lesion, were present in all patients, and Grades II, III radiation dermatitis was observed in four patients. There were no chronic side effects, and no secondary malignancy was observed in the lesions treated with radiation.
|Table 3: Analysis of treatment outcome, relapse, and status at the last follow-up|
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|Figure 1: In early-stage cutaneous T-cell lymphoma, radiotherapy leads to long-lasting remission. A hyperpigmented keratotic scale was observed in the left anterior thigh in one patient (a). After radiotherapy, the lesion disappeared (b)|
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|Figure 2: Treatment during the advanced stage of the disease improved symptoms, such as pain, itching, and hyperkeratosis. Before treatment, one patient experienced severe pain, itching, eczema, hyperkeratosis, and bleeding in the left ear (a). After radiotherapy, the lesion completely disappeared, and a posttreatment biopsy examination confirmed the absence of the previously present lymphoid infiltration. The patient was free of disease in the ear at the last follow-up visit (b)|
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|Figure 3: Survival was analyzed with Kaplan–Meier survival analysis. The 5-year overall survival rate was 66.7% (a), and the 5-year disease-free survival rate was 62.5% (b)|
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| Discussion|| |
In early-stage CTCL, the goal of therapy is to achieve complete remission, while in the advanced stage, the goal is to achieve symptomatic relief and increase the treatment response.
The choice of treatment methods is dependent on the stage of the disease. Because CTCL can last for a long time, treatment is very difficult. Most skin lesions are sensitive to many other therapies, and multiple therapeutic strategies have been attempted.,, A variety of topical and systemic treatments have been utilized based on the extent of skin involvement, the characteristics of the lesions, and the presence of extracutaneous disease. For early-stage CTCL, many studies have recommended skin-directed therapy as a first line of therapy, including topical emollients, steroids, bexarotene gel, ultraviolet B (UVB)/PUVA, and radiotherapy with an electron or photon beam.,, Radiation therapy is known to lead to palliative symptoms and to improve local disease control related to CTCL.,,,,, Many types of radiotherapy, such as kilovoltage photons, electrons, and megavoltage photons with tissue compensation, have been utilized for skin irradiation. In CTCL, electron beam therapy is used for palliative purposes, when one or several isolated cutaneous lesions are treated for symptom control.,,,,,,, Uncommonly, when there is extensive skin involvement, TSEBI is employed. In minimal stage Ia disease, Wilson et al. reported that 21 patients were treated with local radiotherapy. The CR rate to localized RT was 97%. The disease-free survival rate for all patients at 5 and 10 years was 75% and 64%, respectively. Moreover, Piccinno et al. reported that 15 early-stage patients were treated with local radiotherapy. The CR of related lesions was observed in 95% of patients, with the other 5% achieving a PR. Other available studies reported excellent responses to local radiotherapy, with 95%–100% of lesions experiencing complete remission.,,,, In this study, early-stage patients (Stage Ia and Ib) achieved complete remission of all treated lesions. During the follow-up periods, recurrence did not occur for these patients.
In advanced-stage CTCL, no effective treatment options or protocols have been accepted as standard due to the heterogeneity and rarity of the disease., Systemic chemotherapy or radiotherapy, such as TSEBI, has been attempted for treating advanced-stage disease, but the results have been controversial.,, Some studies have reported that combination therapy, including UVA/PUVB or chemotherapy, improves the treatment outcome. However, other studies have suggested that while chemotherapy may result in a comparable response rate, the response is short-lived and may be associated with many complications. Radiotherapy has a long history of use and has evolved to incorporate different techniques, such as TSEBI and localized superficial radiotherapy with electrons or photons., In many studies, most patients treated with TSEBI were reported to experience high rates of disease recurrence., In addition, severe complications associated with TSEBI include grade III skin erythema, dry skin on the entire body, and skin cancer.,, Local radiotherapy has been reported to relieve the symptoms related to CTCL, such as itching, erythema, pain, and bleeding and to delay the progression of early- and advanced-stage disease without severe complications.,,,,,,,,,,,,,,,, Compared to TSEBI, local radiotherapy has advantages, including fewer complications and better patient tolerance. In addition, radiation therapy can control refractory disease more effectively.,,,,,,,,, Xu et al. reported the results of palliative local radiotherapy for the treatment of tumor-stage CTCL. The complete clinical response rate of the radiated sites was 54.5%, the PR rate was 36.4%, and the overall response rate was 90.9%. Moreover, local radiotherapy with psoralen plus UVA and/or interferon-maintaining treatment is an effective palliative therapy in the treatment of tumor-stage MF patients. In this study, advanced-stage patients (Stages IIb and III) achieved a 72.5% CR rate of the irradiated lesions, and the other 27.5% achieved a PR.
In this study, within the irradiated field, complete remission was observed in 82% of patients, and partial remission was observed in 19% of patients after radiotherapy. There was a significantly positive response to the treatment in patients with early-stage disease (P = 0.0427). Recurrence was diagnosed, on average, 5 months (range, 3–7 months) after the end of radiation treatment. Recurrence was not observed within the field of radiation therapy or outside of the field in the early stage. In the advanced stage, two lesions were found in the field of the radiotherapy range, and six lesions were found outside of the field of radiation therapy (total, eight lesions). The recurrence rate was also significantly lower in the early stages of the disease (P = 0.0373).
In early-stage CTCL, in particular radiotherapy can maintain complete remission for long time. In addition, patients treated with radiotherapy with advanced-stage disease experience an improvement in symptoms, such as pain, itching, and hyperkeratosis.
Common radiotherapy dosing regimens in CTCL range from 2000 to 4000 cGy administered in multiple fractions. In addition, Goddard et al. reported excellent results with low-dose and high-dose rate brachytherapy for recalcitrant CTCL of the hands and feet, with reduced acute cutaneous toxic effects. However, other authors reported a dose-response relationship, with higher doses being associated with rates of CR and local control., Cotter et al. evaluated the impact of radiation dose on the local control of 11 MF lesions (53% plaques and 47% tumors). Local recurrence was inversely associated with dose. The rate of local in-field recurrence was 42% with doses ≤10 Gy, 32% for doses of 10–20 Gy, 21% for doses of 20–30 Gy, and 0% when the dose was >30 Gy. In the study of Neelis et al., 70% of the T3 stage MF patients failed to respond because of the dosage, and the CR rate was elevated to 92% in the treated sites after adjusting the doses to 20 Gy. In Xu et al.'s study, a total dosage of 48.55 ± 9.51 (40–74) Gy in an average of 24.55 ± 5.57 (20–40) fractions achieved a high response rate of 90.9% (10 of 11 patients) with no severe toxicity or secondary malignancy. In this study, the total treatment dose ranged from 40 to 50 Gy (median dose, 46 Gy); a 40 Gy radiation dose was administered for stage I, and a 50 Gy radiation dose was administered for Stages II and III, for deep and bulky tumors or for circumferential lesions. These doses achieved a high complete remission rate of 81% and a high response rate of 100%. An acute side effect of Grade II and III radiation dermatitis was observed in four patients, and no severe chronic side effects were observed. In this study, the outcome results were very similar to those of Xu et al.'s study. They assumed that a higher dosage of radiation without obvious side effects may result from different skin conditions and a better tolerance of Asian patients to radiotherapy; more studies on the difference of tolerance to radiotherapy between ethnicities are needed. In conclusion, local radiotherapy should be considered as a treatment for both the early and advanced stages of CTCL.
| Conclusion|| |
Localized conventional radiotherapy is effective for the treatment of the early and advanced stages of CTCL that is refractory to other skin-directed or systemic therapies without the occurrence of severe complications. In addition, radiotherapy can relieve symptoms related to CTCL. To enhance control in the advanced stage, the use of other therapies, such as PUVA, topical agents, and chemotherapeutic agents, in combination with local radiotherapy should be considered.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patients have given their consent for their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
This study was supported by the Research Institute Fund of Clinical Medicine of the Chonbuk National University Biomedical Research Institute of Chonbuk National University Hospital, and this research was supported by the Basic Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning (2017R1A2B4012353).
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]