Efficacy of 8-methoxypsoralen vs. 5-methoxypsoralen plus ultraviolet A therapy in patients with mycosis fungoides

BACKGROUND: Psoralen plus ultraviolet (UV) A (PUVA) is the standard treatment for early stage mycosis fungoides (MF). When 8-methoxypsoralen (8-MOP) is used in PUVA therapy, it often produces intolerance reactions such as nausea, vomiting and headache. OBJECTIVES: To investigate whether 5-methoxypsoralen (5-MOP) is a safe and effective alternative to 8-MOP in PUVA therapy for MF. METHODS: A retrospective database search and chart review was done to identify patients with MF who received PUVA with either 5-MOP or 8-MOP as initial monotherapy at our institution. Between 1990 and 2004, 14 patients [seven men and seven women; mean age 70 years, range 51-82; National Cancer Institute disease stages IA (n = 6) and IB (n = 8)] received 5-MOP, and 24 patients [21 men and three women; mean age 58 years, range 28-89; disease stages IA (n = 11), IB (n = 12) and IIB (n = 1)] received 8-MOP. RESULTS: Twelve of 14 patients (86%) in the 5-MOP group and 22 of 24 (92%) in the 8-MOP group had a complete response to PUVA. These two subgroups of complete responders did not differ significantly in terms of PUVA therapy duration, number of treatments or cumulative UVA dose. They also did not differ significantly in terms of relapse-free rate [8% (one of 12) vs. 23% (five of 22)] or time to relapse [17 months (range 4-31) vs. 14 months (range 4-33)]. Moreover, PUVA maintenance therapy with either 5-MOP or 8-MOP in a subset of patients [26% (nine of 34)] did not affect long-term relapse-free status either. CONCLUSIONS: 5-MOP and 8-MOP have comparable therapeutic efficacy when used in PUVA therapy for MF.     

Narrowband UVB and PUVA in the treatment of mycosis fungoides: a retrospective study

Psoralen plus ultraviolet A (PUVA) is widely used as first-line therapy for treatment of mycosis fungoides. Narrowband ultraviolet B (NB-UVB) has also been shown to be effective for treatment of early mycosis fungoides. The aim of this retrospective study was to analyse the response to treatment and relapse-free interval for PUVA and NB-UVB therapies in mycosis fungoides. Forty patients were treated with PUVA or NB-UVB between 1980 and 2003. All patients had failed to respond to topical therapy or were unwilling to use it. PUVA therapy was used between 1980 and 1997. Thereafter, the choice between PUVA (twice a week) and NB-UVB therapy (three times a week) depended on stage and extent of the disease as well as on how far patients had to travel). Twelve patients (stage IA-IIB) were treated with NB-UVB and 28 patients (stage IA-IVA) with PUVA. No maintenance therapy was given. Six patients (50%) had a complete response, 4 (33%) had a partial response and 2 (16%) had a failed response to NB-UVB but had stable disease. PUVA led to a complete response in 18 (64%), a partial response in 6 (21%) and a failed response in 4 (14%) patients. The median relapse-free interval was 11.5 months in the NB-UVB treated group and 10 months in the PUVA group. The majority of the patients (79%) had stage IA and IB disease. Of these, 6 of 10 (60%) in the NB-UVB group and 13/21 (62%) in the PUVA group had a complete response to treatment. These results show that PUVA and NB-UVB are effective treatments for early mycosis fungoides.     

Photochemotherapy (PUVA) in the pretumour stage of mycosis fungoides: a report from the Scandinavian Mycosis Fungoides Study Group

Fifty-one patients with mycosis fungoides of pretumour stage were treated with oral 8-MOP and UVA photochemotherapy (PUVA). Complete remission was induced within 2--3 months in 58% of the cases. Twenty-seven patients are still in remission on maintenance therapy 9--53 months after starting treatment. In 9 cases PUVA treatment was stopped due to therapeutic failure and in another 15 cases due to various side effects. Maintenance therapy was given weekly, monthly, or at even longer intervals. Maintenance at long intervals seems preferable.     

Narrow band UVB therapy in early stage mycosis fungoides. A study of 23 patients

IntroductionPhototherapy is effective for mycosis fungoides. Narrow band UVB (UVB₁) therapy is being used as an alternative to PUVA therapy for its efficacy and less adverse events. The objective of the study was to determine the efficacy of narrow band UVB therapy in early stage mycosis fungoides.MethodsIt is a retrospective study of 23 patients with stage IB mycosis fungoides that have received UVB₁ therapy following the phototherapy protocol of the Spanish Photobiology Group.ResultsThirteen patients (57 %) had a complete response, eight patients (35 %) had a partial response and two patients (8 %) did not respond. Half of the patients with complete response (n = 6) relapsed after one year of follow-up.ConclusionsWe consider that UVB₁ therapy is a good alternative for treatment of early stage mycosis fungoides, although the disease-free period is short.     

The effect of psoralen plus ultraviolet A in vitro in HUT-78 enhances by 5-aminolevulinic acid

BACKGROUND: Sezary syndrome and mycosis fungoides are forms of cutaneous T-cell lymphoma, and in the early stage of these diseases psoralen plus ultraviolet A (PUVA) is one of the treatments of choice. Photodynamic therapy using 5-aminolevulinic acid (ALA-PDT) is an effective, non-invasive, and safe treatment for most superficial skin cancers. In order to obtain greater efficacy of PUVA, we investigated the synergistic anti-tumor effects of ALA-PDT and PUVA using 8-methoxypsoralen (8-MOP) and a UVA lamp. METHODS: The in vitro effects of PUVA and ALA-PDT and their combination in HUT-78 cell line from human SS were determined by MTT assay. RESULTS: In our results, cell proliferation compared with controls was inhibited to 53.2% with UVA alone, 52.3% with 1 microM 8-MOP, 43.8% with 100 microM ALA, and 19.2% with combined 8-MOP and ALA. CONCLUSION: Combined use of ALA and PUVA using 8-MOP and UVA lamps, which are widespread in Japan, had a strong anti-tumor effect in vitro. Combined treatment with ALA-PDT and PUVA using a UVA lamp appears to have a strong treatment effect.     

The Effects of Non-Interval PUVA Therapy on the Plaque Stage of Mycosis Fungoides

The effectiveness of non-interval topical PUVA treatment was studied in four patients with mycosis fungoides at the plaque stage. Five regions of each patient were exposed to UVA immediately, 30 minutes, 60 minutes, 90 minutes, and 120 minutes, after topical application of 8-methoxypsoralen, respectively. The effects of these treatments were evaluated by clinical appearance and histological findings after the 20th treatment. All five regions were more improved clinically and histologically than the control region, which was not given PUVA therapy. There were no clear differences clinically among these five regions. Biopsy specimens from each region revealed the disappearance of epidermotropism and a marked decrease in atypical mononuclear cell infiltrations in the dermis. From these data, we concluded that there were no clear differences between these five treatments clinically or histologically and that non-interval PUVA therapy is useful for the early stages of mycosis fungoides. To our knowledge, this is the first report of non-interval PUVA therapy for mycosis fungoides.     

Photochemotherapy in cutaneous T cell lymphoma and parapsoriasis en plaques. Long-term follow-up in forty-three patients

Forty-three patients with clinical plaque- and tumor-stage mycosis fungoides, the erythrodermic/Sézary syndrome variant of mycosis fungoides, and parapsoriasis en plaques were treated with oral psoralens and ultraviolet A (PUVA). Pretreatment skin biopsies, evaluated by light microscopy, revealed seventeen diagnostic, seventeen suggestive, and nine nonspecific specimens. Clinical and histologic parameters were followed for an average of 38.4 months (range, 4-67 months). Twenty-five patients had complete clearing, and fourteen did not respond. Most patients in the complete-response group had either plaque lesions of mycosis fungoides or parapsoriasis en plaques prior to PUVA. Most patients in the no-response group had either tumor lesions or the erythrodermic/Sézary mycosis fungoides at the start of PUVA. In the no-response group the treatment modalities used prior to PUVA were twice the number used in the complete-response group. Patients in the complete-response group had clearing of their lesions after an average PUVA dose of 117 joules/cm2. Relapse occurred in seventeen patients after an average remission time of 6.3 months and responded to additional PUVA. Patients whose skin remained clear after the first course of PUVA continued to have clear skin for up to 58 months, with an average complete remission of 29.5 months by the end of the study period. Histologic evaluation before PUVA and at clearing revealed a definite trend toward a normal microscopic picture, but at least a mild inflammatory infiltrate usually persisted. At the end of the study period, the lesions of ten patients had entirely cleared for an average of 44 months, the lesions of five had cleared during a second course of PUVA, five had stable limited-plaque disease while receiving maintenance PUVA, eleven were undergoing electron beam radiation therapy or chemotherapy for progressive disease, ten had died, and two patients were lost to follow-up. Therefore, in the early stage of mycosis fungoides, PUVA may induce significant disease-free intervals. Prior treatment with a variety of modalities, the patient's age, and/or the duration of disease may affect response to PUVA.     

Correlation between 8-methoxypsoralen bath-water concentration and photosensitivity in bath-PUVA treatment

BACKGROUND: Bath-PUVA treatment, originally established in Scandinavia, offers several advantages over oral PUVA and has become increasingly popular in recent years. Outside Scandinavia 8-methoxypsoralen (8-MOP) is the prevailing photosensitizer for this PUVA modality and is used arbitrarily in a wide range of concentrations. Up to the present, data are lacking on the impact of 8-MOP bath-water concentration on UVA dosimetry. OBJECTIVE: We investigated the influence of increasing 8-MOP bath-water concentrations on photosensitivity in bath-PUVA treatment. METHODS: Fifteen healthy volunteers without abnormal photosensitivity or recent exposure to ultraviolet radiation were included in an intraindividually controlled comparison study. In all volunteers the minimal phototoxic dose (MPD) was determined on the volar side of their forearms after immersion for 20 minutes in 4 different 8-MOP bath-water concentrations (0.5, 1, 2.5, and 5 mg/L). The correlation between 8-MOP concentration and photosensitivity (defined as the reciprocal value of the MPD) was analyzed by linear regression analysis. In addition, the time course of erythema formation and the UVA dose-erythema response curve was assessed for each psoralen concentration. RESULTS: The median MPD and the 25%-75% interquartile were 5.7 J/cm(2) (5.7-8), 4 J/cm(2) (4-5.7), 2.8 J/cm(2) (2.8-5.7), and 2 J/cm(2) (2-2.8) at an 8-MOP concentration of 0.5, 1, 2.5, and 5 mg/L, respectively. Linear regression analysis revealed a significant correlation between 8-MOP bath-water concentration and photosensitivity (r = 0.98; P =.019). Bath-PUVA-induced erythema peaked after a median time interval of 3 days, with a range of 2 to 4 days. The slope of the UVA dose-erythema response curve was similar for all psoralen concentrations. CONCLUSION: UVA dose requirements in bath-PUVA treatment decrease linearly with increasing 8-MOP concentrations. A single MPD assessment at 72 hours after the UVA exposure is inappropriate for accurate determination of the patients' photosensitivity. The hazard of wrong UVA dosimetry is comparable at all psoralen concentrations.     

Photochemotherapy in mycosis fungoides]

Nineteen patients with mycosis fungoides (m.f.), without involvement of lymph nodes and/or internal organs, were treated with oral photochemotherapy (PUVA). After four to five weeks of PUVA therapy (four irradiations/week) complete remission of erythematous and infiltrative plaques occurred; tumorous m.f. lesions also responded to treatment but required longer treatment times. After complete resolution of m.f. lesions the patients were controlled regularly, the observation periods ranging from 6 to 27 months. When recurrences occurred the initial treatment schedule was resumed. Recurrences, more often seen in the tumorous m.f. stage, responded to PUVA equally well as the initial lesions. PUVA therapy of m.f. is thus more effective than conventional UVB-irradiation and less problematic than treatment with cytotoxic agents or ionizing radiation. Present experience indicates that PUVA represents the treatment of choice in early stage m.f.     

Narrowband UVB as an effective substitute for psoralen plus UVA: lessons from a psoralen shortage

From March to August 2010, there was a shortage of encapsulated liquid 8-methoxypsoralen (8-MOP), the psoralen used for bath psoralen plus UVA (PUVA) in Toronto, Canada. Patients were forced to discontinue bath PUVA treatment and were transitioned to other therapeutic modalities, including narrowband UVB (nbUVB). A retrospective chart review was conducted of all patients who discontinued bath PUVA due to the unavailability of 8-MOP, with a focus on those who were switched to nbUVB. Sixty-three patients discontinued PUVA, 39 of whom were switched to nbUVB. Fifteen of 17 patients with mycosis fungoides (MF) who were switched to nbUVB improved, and patients with earlier-stage disease were more likely to improve. Ten of 13 (77%) psoriasis patients improved with nbUVB, including two patients whose psoriasis cleared completely. All three small-plaque parapsoriasis patients who switched to nbUVB had complete clearance of their lesions. In conclusion, nbUVB may be a suitable alternative for patients with MF, small-plaque parapsoriasis and psoriasis who cannot access PUVA therapy.     

THE TREATMENT OF MYCOSIS FUNGOIDES WITH PUVA*

Twenty patients with mycosis fungoides were treated with photochemotherapy using oral psoralens and long wave ultraviolet light (PUVA) over a two-year period. PUVA was effective in producing a diminution of cutaneous deposits of mycosis fungoides with each clinical pattern of presentation. In most patients complete clearing could not be achieved, and in those considered free of disease, sustained total clearing off PUVA could not be maintained. Lack of response to the effect of PUVA if reinstituted for recurrence of disease did not occur. The palliative use of PUVA for the treatment of mycosis fungoides is recommended.     

Total cutaneous electron beam therapy of mycosis fungoides

Electron beam irradiation of the entire skin surface was used to treat 25 patients with mycosis fungoides from 1977 to January 1988. A plexiglas screen was used to reduce the energy of the 8 MeV beam of a Sagittaire linear accelerator to 4 MeV. A total dose of 30 Gy was delivered in 12 fractions over days. This series includes 17 men and 8 women with a mean age of 44 years (range 13-78 years) and a mean follow-up of 34 months (range 6-92 months). The following-up staging system was used: stage A: superficial lesions covering less than 50 p. 100 of the body surface; stage B: superficial lesions covering more than 50 p. 100 of the body surface; stage C: tumors of the skin, lymph nodes and/or visceral organs, Sezary's syndrome. All stage A patients achieved complete remission. One developed recurrent disease in a very limited area 17 months after radiation therapy. No stage A patient died of mycosis fungoides. 6/9 stage B patients achieved complete remission; 4 of these developed recurrent disease localized to the skin 6 to 13 months after electron therapy. These recurrences were controlled by topical nitrogen mustard, puva therapy or localized irradiation. 1 patient showed no response and died of cutaneous mycosis fungoides. 5/10 stage C patients obtained complete remission but all relapsed within a mean period of 7 months. 4/5 of the patients not responding to electron therapy died of their disease and one is alive 16 months after completion of treatment.(ABSTRACT TRUNCATED AT 250 WORDS)     

Langzeitergebnisse der Ganzhautelektronenbestrahlung (GET) in der Therapie der Mycosis fungoides

BACKGROUND AND OBJECTIVE: Total skin electron beam therapy (TSEBT) is an important therapeutic option for the treatment of mycosis fungoides. The aim of this study was to find out long term results in 10 patients with the clinical and histological diagnosis of mycosis fungoides. PATIENTS AND METHODS: Between 1982 and 1997 we performed a total skin electron beam therapy in 10 patients. One patient was in stage I A; 5, in stage I B; 3, in stage II B; and one, in stage IV A. The indication for TSEBT was disease progression in spite of PUVA therapy. The doses of electron beam therapy were 30- 36 Gy at 5-6 MeV. In 7 of 10 cases additional local electron beam therapy was given, because individual lesions persisted or recurred after a short time. RESULTS: Complete remission was achieved in 5 patients. The follow- up has been up to 10 years. One patient died of systemic lymphoma 10 years after electron beam therapy. Three patients died of illnesses unrelated to mycosis fungoides. One patient developed a high grade T-cell lymphoma. CONCLUSIONS: Total skin electron beam therapy is a very effective, but technically difficult therapy for mycosis fungoides, especially in stage I B and II B. Particularly interesting has been the long duration of complete response of three patients, who had follicular mucinosis preceding their mycosis fungoides.     

Photochemotherapy in mycosis fungoides

Thirty-eight patients with various stages of mycosis fungoides were treated with oral 8-meth-oxypsoralen and longwave ultraviolet radiation (PUVA). The majority responded well to PUVA, especially those with the early stages of the disease. The response in patients with tumours was not as good, with less than half improving slowly and recurrences were frequent. Histological studies showed in most patients a marked clearing of the cellular infiltrate in the epidermis and dermis in the PUVA treated lesions. It appears that PUVA is an effective treatment for the early stages of mycosis fungoides and is of some use in the management of more advanced disease.     

Narrow-band UVB in the treatment of early stage mycosis fungoides: report of 16 patients

Although early stage mycosis fungoides (MF) has a generally good prognosis, and long-term survival rates with current therapies (UVB, photochemotherapy, topical nitrogen mustard, electron beam radiotherapy) are similar, there is concern regarding their potential side effects. It has been reported that the same effective UVB dose is safer than PUVA in terms of carcinogenicity, and that it produces fewer side effects. Our aim was to evaluate the effect of narrow-band UVB in the treatment of early stage MF. Sixteen patients (seven males, nine females; mean age, 40 years) with early stage MF received TL-01 phototherapy three times per week using a standard protocol. Twelve patients (75%) had complete response in a mean of 27.9 treatments, three had partial response, and one no response. Upon discontinuation of treatment, six patients with complete response relapsed in a mean time to relapse of 4.5 months. The present study indicates that narrow-band-UVB is an effective treatment modality for early stage MF.     

Retinoids plus PUVA (RePUVA) and PUVA in mycosis fungoides, plaque stage. A report from the Scandinavian Mycosis Fungoides Group

Sixty-nine patients with mycosis fungoides, plaque stage, were treated in an open study with photochemotherapy (PUVA) or the combination of oral retinoids and PUVA (RePUVA). The response rate of Re-PUVA was equal to that of PUVA, with complete remission in 73% and 72%, respectively. Remissions were obtained with fewer PUVA sessions, and with a lower UVA dosage, if PUVA was combined with retinoids. A lower UVA dosage was needed if treatment was given four times weekly in stead of twice weekly. The duration of the remissions tended to be prolonged if retinoids were given as maintenance therapy.     

Treatment of a case of mycosis fungoides and one of parapsoriasis en plaque with topical PUVA using a monofunctional furocoumarin derivative, 4,6,4'-trimethylangelicin

A case of plaque stage mycosis fungoides and one of parapsoriasis en plaque were treated with topical PUVA therapy using a monofunctional furocoumarin derivative, 4,6,4'-trimethylangelicin (TMA). Both patients showed complete clearance of eruptions within 16 treatments. The therapeutic effectiveness of TMA was confirmed by the fact that those eruptions exposed to UVA alone, without TMA application, showed slower and less significant improvement. Histologically, dermal infiltrates of mycosis cells and associated epidermotrophism disappeared almost completely in response to TMA PUVA. No side effects or changes in values in laboratory examinations were observed during treatment.     

Generalized syringotropic mycosis fungoides responsive to total skin electron beam therapy

A case of syringotropic mycosis fungoides without internal organ involvement received total skin electron beam therapy (TSEBT) and evolved into poikilodermatous mycosis fungoides. Subsequent oral psoralen plus ultraviolet A (PUVA) therapy achieved complete remission. The value of TSEBT for syringotroopic mycosis fungoides is illustrated in this case.     

Treatment of cutaneous T-cell lymphoma with extracorporeal photochemotherapy

Background Cutaneous T-cell lymphoma (CTCL) and its leukemic erythrodermic form (Sézary syndrome) are malignancies cies of CD4+ T lymphocytes. Extracorporeal photochemotherapy (ECP) selectively affects autoreactive as well as malignant T lymphocytes. The efficacy of ECP depends strongly upon adequate serum/buffy coat levels of the photosensitizer 8-methoxypsoralen (8-MOP). The resorption of orally applied 8-MOP vanes inter- and intraindividually within a broad range, meaning that adequate therapeutic drug levels cannot always he achieved. Therefore, since July 1994 we have exclusively used a liquid 8-MOP preparation which is added directly into the buffy coat fraction of the ECP circuit, resulting in constant high drug levels of approximately 190 ng/ml. Twelve CTCL-patients (six with Sézary syndrome, six with mycosis fungoides received between six and 25 ECP treatments. Some of them had undergone previous therapy without success. Results All patients with Sézary syndrome declared a distinct reduction in intensity of pruritus. Three patients who received liquid 8-MOP extracorporeally showed a partial remission on the basis of skin scores. Of the patients receiving 8-MOP orally, two remained clinically unchanged and one showed a progression of the disease. In these cases, subtherapeutic 8-MOP plasma levels were often found. Of the six mycosis fungoides patients one achieved complete and two partial remission: another two patients showed minor response. These five patients were treated with liquid 8-MOP. One patient showed no change in skin lesions; he had received 8-MOP orally and achieved subtherapeutic photosensitizer plasma levels. Conclusion Our treatment protocols confirm the beneficial effects of ECP on CTCL at any stage, but it seems that adequate ECP efficiency is ensured only when an 8-MOP solution is applied extracorporeally.     

Plasma levels of 8-methoxypsoralen following PUVA-bath photochemotherapy

Administration of 8-methoxypsoralen (8-MOP) in a dilute bath water solution is an effective therapeutic alternative to oral PUVA therapy, avoiding systemic side effects, offering better bioavailability of the psoralen and requiring much smaller amounts of UVA for induction of therapeutic effects. To obtain exact data about the percutaneous absorption of 8-MOP during a psoralen bath, the plasma levels of the drug were determined in 26 patients with different skin diseases by a reverse high-performance liquid chromatographic method. Fifteen patients receiving oral PUVA therapy (0.8 mg 8-MOP/kg body weight) served as a positive control group. Bath solutions were prepared by diluting 15 ml of 0.5% stock solution of 8-MOP in 150 l of bath water (0.5 mg/l, 37°C). Blood samples were drawn from patients 5, 30, 60, 120 and 180 min after the bath. In the oral PUVA group, blood samples were obtained 1½ h after administration of the drug. In 23 of 26 patients, 8-MOP levels were undetectable in every blood sample. After 30 min, two patients showed detectable levels of 8-MOP (5 ng/ml, 7 ng/ml), while 60 min after the PUVA bath 8-MOP was detectable in only one volunteer (5 ng/ml). In patients receiving oral 8-MOP therapy, serum levels varied between 45 and 360 ng/ml 1½ h after drug administration. Our data confirm extremely low 8-MOP levels resulting from 8-MOP bath water treatments and provide confirmation of the absence of systemic side effects in patients who are undergoing PUVA-bath therapy.