Palliative Local Radiotherapy in the Treatment of Tumor-stage Cutaneous T-cell Lymphoma/ Mycosis Fungoides

Chen-chen Xu, Tao Zhang, Tao Wang, Jie Liu, and Yue-hua Liu

Department of Dermatology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China

MYCOSIS fungoides (MF), the most common subtype of cutaneous T-cell lymphoma, has diverse clinical manifestations, mostly confined to the skin. Skin lesions of MF can be red patches, plaques, or even tumors. MF can be classified into 4 stages according to tumor-node- metastasis (TNM) staging system, which defines the extent of skin lesions, number of lymph nodes involved, and visceral organ involvement.1The TNM staging system also has prognostic value, as the survival of the patients with advanced stage MF is much lower than that of the patients with stage IA MF.2

Numerous topical and systematic therapeutic strategies have been applied for palliation and treatment of the disease, including topical nitrogen mustard, topical bis-chloroethylni- trosourea (BCNU), oral psoralen plus total skin ultraviolet light A irradiation (PUVA), total skin electron beam therapy (TSEBT), extracorporeal photochemotherapy (ECP), single- or multiple-agent chemotherapy, interferons, adenosine analogs, retinoids, and monoclonal antibody therapy.3

Of all these treatments, radiation has been used as an effective method in the management of patients with MF since 1902 because of the radiosensitivity of neoplastic T-cells. TSEBT became available in the early 1950s and has been developed to be an effective modality to cure patients with T1, T2, and even T3 stage MF.4However, complications of this therapy are sometimes severe and most patients treated with TSEBT often experience recurrence, especially the patients of advanced stage MF. Localized radiation therapy, mainly recommended in the treatment of single-lesion and stage IA MF, has been studied and proven effective in both curative and palliative treatments in recent years.5For patients with more advanced MF, palliative radiotherapy is offered in combination with systemic therapy, such as chemotherapy and PUVA, to alleviate symptoms and delay progression.6

It has been well documented that patients with advanced stage MF may suffer from painful ulcerations, bleeding, disfigurement, and impaired quality-of-life,7and most who present with tumor-stage MF ultimately die of this disease. Fortunately, a few researches showed that local treatments, such as local radiotherapy, could alleviate symptoms and delay progression with less toxicity than aggressive chemotherapy in those patients.4However, few publications provided enough details and clinical results of these treatments.

In this paper, we report the results of 11 patients with tumor-stage MF who were treated with palliative local radiotherapy and followed up for 5 years.

PATIENTS AND METHODS

Patients

From January 2008 to January 2013, a total of 121 pathologically and clinically diagnosed MF patients were treated and followed-up in the Department of Dermatology and the Department of Radiotherapy of Peking Union Medical College Hospital, of which 11 patients with T3 stage MF received local radiotherapy. Information of the 11 patients are listed in Table 1.

All the patients underwent a complete physical examination of the skin surface and palpable lymph nodes. Metastatic lesions were evaluated with chest X-ray, computed tomographic scan of abdomen and pelvis, and bone marrow biopsy before staging. All the patients were staged according to the TNM staging system.

Treatments

None of the 11 patients received prior radiotherapy of any type, which was defined as any treatment applied before the decision of radiation. All the 11 patients had been previously treated with systemic interferon and/or PUVA, but were deemed to be refractory to the regimen.

All the patients were treated with local electronic beam irradiation with a mean total dosage of 48.55±9.51 Gy (range: 40-74 Gy) in an average of 24.55±5.57 (range: 20-40) fractions, 5 fractions per week. PUVA and interferon were adopted as adjuvant treatments, the details of which are presented in Table 2. An asdjuvant treatment was defined as that given to patients immediately following a complete response (CR) or a good partial response (PR) after local radiotherapy.8Salvage therapy was defined as treatment initiated after failure of any adjuvant regimen to keep the cutaneous skin surface being relapse-free following local radiotherapy.9Three patients received systemic chemotherapy as salvage therapy after failure of adjuvant PUVA and/or interferon therapy.

Table 1. General information of the 11 patients with T3-stage mycosis fungoides (MF)

Table 2. Treatment outcome and other therapies

Statistical analysis

SPSS 17.0 software was applied in the statistical evaluation of age, sex, course of disease, and following-up period of the patients analyzed. Data were expressed as means±SD. Response to local radiotherapy was classified as CR, PR, or no response of the radiation fields at 4-8 weeks after completion of local radiotherapy. CR was defined as >75% clinical regression of all lesions in the radiation field, and PR was defined as >50% and <75% regression of the lesions in the radiation field,10no response was defined as <50% regression of the lesions or progression of the lesions.6

RESULTS

General information of the patients

The median age of the 11 patients was 53.36±14.45 years, ranging from 32 to 79 years. There were 6 males (54.5%) and 5 females (45.5%), with the female-to-male ratio being 1∶1.2. The average course of the disease was 10.82±3.37 years (range: 6-16 years).

Treatment outcome

The median follow-up period was 55.27±29.30 months (range: 13-103 months) after the completion of local radiotherapy. Eight patients were alive by the end of the follow-up period and 3 patients died of the disease. Besides the irradiated regions, lesions of the 8 patients were controlled well with PUVA plus/or interferon therapy.

CR of the radiated sites was observed in 6 patients (54.5%) and PR in 4 patients (36.4%). And the overall response rate (CR+PR) was 90.9%. One patient had persistent ulceration after 20 fractions of radiotherapy, which was defined as no response to radiation. PUVA plus interferon therapy in that case was continued in the follow-up period and the lesion improved gradually (Table 2).

Adjuvant therapy and salvage therapy

Adjuvant therapies were applied for all the 11 patients. All (100%) received nitrogen mustard lotion (250 mg/L water solution), 7 patients (63.6%) received PUVA, 7 patients (63.6%) received interferon, and 1 patient (9.1%) received narrow-band ultraviolet B irradiation as adjuvant therapies. In addition, 3 patients (27.3%) received systemic chemotherapy as a salvage therapy when adjuvant therapies failed to maintain the relapse-free status of the lesion and the disease aggravated, and the three patients finally died of MF.

Toxicities

All the patients developed mild atrophy and dryness at the site of original lesion, but no severe side effects during therapy. Two patients experienced mild ulceration after increasing the dose of radiotherapy. One patient showed mild erythema at the radiated site. Furthermore, 4 patients showed pigmentation at the treated sites as the most frequent chronic toxicities of radiotherapy in this study. No secondary malignancies were observed in the radiation locations.

DISCUSSION

MF is a heterogeneous cutaneous T-cell lymphoma. Numerous topical and systemic treatments have been utilized based on the extent of skin involvement, characteristics of skin lesions, extracutaneous diseases, and toxicities. However, no treatment options or protocols have been accepted as stardard for MF patients, especially for patients with advanced tumor-stage MF, due to heterogeneity and rarity of this disease. Radiotherapy could be one of the most effective methods because of the radiosensitivity of neoplastic T cells.4TSEBT is likely the most effective skin-targeted therapy for patients in different stages of the disease, including patients with T3 stage MF. Navi et al11reported a research of Stanford University Medical Center involving 180 patients with T2 and T3 stage MF treated with TSEBT. Of their patients, 77 had T3 stage disease, and the CR rate for the T3 group was 47%. Most patients treated with TSEBT experienced persistence of symptoms or disease recurrence. Also, complications of TSEBT are sometimes severe, including erythema, dry skin of the whole body, and cutaneous carcinoma. The authors also assumed from the results that T3 stage patients are more likely to develop extracutaneous disease and die from MF than those with less advanced disease.11Therefore, combination therapy, including chemotherapy, could be utilized to improve the clinical outcomes. Although chemotherapy may result in a compatible response rate, its response is short-lived and could be associated with significant myelosuppression and infectious complications, which is often fatal to tumor-stage MF patients.12And there is no evidence that any such therapeutic options could prolong overall survival.3

Localized radiation therapy has mainly been studied and proven effective in the treatment of single-lesion and stage IA MF. Furthermore, it has been reported that local radiation therapy can alleviate symptoms and delay progression of advanced MF with less toxicities.5Acute and long-term complications include dermatitis, skin atrophy, and telangiectasia. The advantages of local radiotherapy compared with TSEBT include less toxicities and better tolerance. In addition, it does not preclude the application of PUVA, nitrogen mustard, or other therapies as adjuvant or salvage therapies, as required for future recurrence.3

No consensus has been achieved on the total dose or fractions of irradiation in palliating tumor-stage MF. Wilson et al13concluded in a research of minimal stage IA MF that a minimum surface dose of 24 Gy was necessary for optimal local control. To administer the dose too low may result in local or distant failures.14In the study of Neelis et al,670% of the T3 stage MF patients fail to response because of dosage and CR rate was elevated to 92% in treated sites after adjusting doses to 20 Gy. In this study, the total dosage of 48.55±9.51 Gy (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 toxicities or secondary malignancy. We assume that the higher dosage of radiation without obvious side effects may result from the different skin condition and better tolerance to radiotherapy of Asian patients, and more studies are needed on the differences of tolerance to radiotherapy between ethnicities.

Limitations of this study are primarily related to its retrospective nature. Furthermore, the use of other therapies before and in combination with local radiotherapy is another limitation, which is difficult to adjust due to the clinical severity of the diseases.

In conclusion, the present study confirms that local radiotherapy is an effective palliative therapy in the treatment of tumor-stage MF. It induces a high response rate with little toxicity. Therefore, we suggest the application of local radiotherapy plus PUVA and/or interferon regimen for palliation and symptom control in patients with tumor-stage cutaneous T-cell lymphoma/MF.

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