14

&~~~hl~ References I. Hennine 0, Wattel E, Gessain A, et al. Adult T cell leukaemia: a review of established and new treatments. BioDrugs 1998 Dec; 10 (6): 447-62 2. Shimoyama M, and members of the lymphoma study group. Diagnostic criteria and classification of clinical subtypes of adult T-celileukaemiallymphoma. Br J Haematol1991; 79: 428-39 3. Bunn Jr PA, Schechter GP, Jaffe E, et al. Clinical course of retrovirus-associated adult T-cell lymphoma in the United States. N Engl J Med 1983; 309 (5): 257-64 4. Shimoyama M. Treatment of patients with adult T-cell leukaemialymphoma: an overview. In: Takasuki K, Hinuma Y, Yoshida M, editors. Advances in adult T-cell leukaemia and HTLV-I research: Japan scientific societies press. Gonn Monographs on Cancer Research 1992; 39: 43-56

5. Gill PS, Harrington Jr W, Kaplan MH, et al. Treatment of adult T-cell leukaemia-lymphoma with a combination of interferon alfa and zidovudine. N Engl J Med 1995; 332 (26): 1744-8 6. Hermine 0, Bouscary D, Gessain A, et al. Brief report: treatment of adult T-cen leukaemia-lymphoma with zidovudine and interferon alfa. N Engl J Med 1995; 332(26): 1749-51 7. Bazarbachi A, Hermine 0. Treatment with a combination of zidovudine and alfa-interferon in naive and pretreated adult T-cen leukaemiallymphoma patients. J Acquir Immun Defic Synd Hum Retrovirol 1996; 13 Suppl. 1: S 186-90 8. Oguma S, Imamura Y, Kusumoto Y. Accelerated declining tendency of human T-cell leukaemia virus type I carrier rates among younger blood donors in Kumamoto, Japan. Cancer Res 1992; 52: 2620-6 9. Yamaguchi K. Human T-Iymphotropic virus type I in Japan. Lancet 1994; 343: 213-6

Skin cancer with PUVA: how much do we know? Photochemotherapy with psoralens and long-wave ultraviolet radiation in the A range (PUVA) is a standard treatment for psoriasis. However, there is increasing concern about the long-term carcinogenic effect of therapy. An increased risk of squamous cell carcinoma associated with oral PUVA is well recognised, but recently it has also been suggested that there may be an increased risk of malignant melanoma. Whether there is an increased risk of melanoma following PUVA treatment has still to be confirmed; however, patients for PUVA should be carefully selected and rigorously followed.

TT,ere is increasing concern about the long-term carcinogenic effect of therapy Psoralens used in PUVA can be given orally or administered topically. The type of psoralen used and the route of administration may affect the actual dose of ultraviolet A (UVA) required and thus the risk of cancer. However, there are many confounding factors that require investigation before any firm conclusions can be drawn.

Few treatment choices for severe disease Psoriasis is a chronic and intractable skin disease affecting I to 3% of the population.[l] For severe and extensive forms of psoriasis a number of treatment options are available including: photochemotherapy, methotrexate, cyclosporin and retinoids. Unfortunately all these treatments have potentially serious adverse effects.

to be highly effective with most patients experiencing complete remission for a fairly long duration.[l] However there are increasing concerns over the potential long-term carcinogenic effect of PUVA therapy. Systemic methoxsalen and PUVA is associated with an increased incidence of non-melanoma skin cancer[l] and more recently, an increased incidence of malignant melanoma has been reportedP] However, there is encouraging data to suggest that trioxsalen bath PUVA does not appear to increase the risk of developing skin cancer)3]

Oral or topical route the best? Numerous studies have confirmed the efficacy of oral and topical psoralens and PUVA in various forms of psoriasis.[I] The most commonly used psoralens are summarised in table 1. Psoralens sensitise the skin to the effects of long-wave UVA radiation (wavelength 320 to 400nm). The photochemical reactions appear to inhibit DNA synthesis and subsequently cell division within the rapidly dividing psoriatic epidermis.[I] For patients with localised forms of psoriasis and palmoplantar pustular psoriasis, topical psoralens are the treatment of choice.[l] They have the advantage of avoiding some of the adverse effects of oral treatments, particularly nausea.[1] However, for patients with more generalised psoriasis the choice of oral or topical PUVA is probably due more to practical convenience and regional preference; trioxsalen bath PUVA has been particularly favoured in some of the Scandinavian countries)l]

Less UVA with trioxsalen bath Long remission with PUVA? PUVA is probably the most extensively studied of the available treatments for psoriasis, and has been shown

Vol. 15, No.3; February 14, 2000

Treatment with trioxsalen bath PUVA has been shown to be highly effective requiring lower numbers of treatments and lower doses of UVA than oral PUVA.[l] Bath PUVA

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with trioxsalen requires only 10% of the UVA radiation dose given with oral methoxsalen PUVA.[4] This lower UVA dose may be possible because trioxsalen is 10 to 15 times more phototoxic than methoxsalen)3] Moreover, it should be noted that the radiation dose with methoxsalen bath PUVA is also lower (25%) than that required with oral methoxsalen PUVA)4]

Increased risk of skin carcinomas? One of the adverse effects of oral PUVA treatment is an increased incidence of non-melanoma skin tumours.[!] Squamous cell carcinomas of the skin most commonly occur but basal cell carcinomas have also been reported. The incidence of squamous cell carcinoma was 6.2 times higher than in the general population in an epidemiological study of 4799 patients receiving systemic treatment with methoxsalen PUYA.l5] Although potentially life threatening, such tumours are slow growing and can be managed by appropriate treatment and follow-up)!] Of more concern is the potential link between oral PUVA therapy and malignant melanoma which has been implicated in a large, long-term follow-up study)2] This is especially worrying because melanoma is often fast growing and even close monitoring of patients may not be sufficient to prevent death.

Oral PUVA link with melanoma? About 15 years after the first PUVA treatment the risk of malignant melanoma is increased approximately 5-fold, according to the results of a long-term follow-up studyP] The study of 1380 patients with psoriasis, recorded a total of 11 melanomas in 9 patients, with 8 of the melanomas occurring 13 years or more after the first PUVA dose.f2] Melanoma was more likely to occur in patients who had received 250 or more doses of PUVA.[2] Although they appear convincing these results have been criticised for the following reasons)!] • there was no control group, so it is not certain whether there is a higher risk of melanoma in patients with psoriasis regardless of the treatment they receive • the relative risk calculations were based on cancer incidence figures in the US (Surveillance, Epidemiology, and End Results data) which only sample approximately 10% of the population • some of the patients were at greater risk for melanoma because of a family history of melanoma.

Table 1. Psoralens for psora len plus ultraviolet A (UVA) treatment[1.3.] Drug name

Comments

Dose

Standard treatment

0.6 mg/kg

Better gastrointestinal tole ranee than methoxsalen

0.6 mg/kg

Oral Methoxsalen (8-methoxypsoralen) t 5-Methoxypsoralen t

Topical Methoxsalen

0.1-5.0 mg/Lb Used for localised treatment and in whole body baths a Trioxsalen Used in whole body 0.08-0.Smg/L b (trimethylpsoralen)t baths a t Methoxsalen and its derivatives are not available in Australia; 5-methoxypsoralen is not available in Spain and the US; trioxsalen is not available in Germany and Spain [in France. trioxsalen Is also available for oral administration (adult dose of 20mg) and for topical application as a 1% solution]. a The duration of the bath Is 15 to 20 minutes, with UVA irradiation administered within 30 minutes of the bath. The initial dose UVA dose should be a30% of the minimal phototoxic dose. b The dose depends on the light sensitivity of the patient. The psora len is dissolved in 150L of warm bath water (30- 3JOC).

carcinoma or cutaneous malignant melanoma, according to results of a combined analysis of two previously published studies)3] The cancer incidence for a total of 944 Swedish and Finnish patients undergoing treatment for psoriasis was compared with the expected numbers of cases based on national cancer incidence rates in the respective countries. The mean follow-up time was 14.7 years for squamous skin cell carcinoma or cutaneous malignant melanoma. A total of 3 patients developed squamous cell carcinoma and 2 developed malignant melanoma giving standardised incidence ratios of 1.1 (95% CI 0.2-3.2) and 0.9 (95% CI 0.1-3.2) respectively. Combining the studies gave sufficient statistical power to conclude that the risk of squamous cell carcinoma was lower than that reported for oral methoxsalen PUVA.[3] However it was noted that only a small proportion of patients had been exposed to high doses of PUVA and that further long-term follow-up data was required to conclusively determine the carcinogenicity of trioxsalen bath PUVA. Table 2. Minimising skin cancer risk in patients treated with psoralen plus ultraviolet A (PUVA)[I.4J Follow PUVA treatment guidelines

Less risk of skin cancer with trioxsalen bath PUVA Bath PUVA using trioxsalen does not appear to be associated with an increased risk of squamous skin cell

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Provide rigorous follow-up Exclude patients with a history or family history of melanoma Limit the number of treatments to :<;;200

Vol. 15, No.3; February 14, 2000

16

&~~~hl~ Are other cancers increased? Although the overall risk of other cancers was not increased in the above study an increase in the incidence ofrt'.,al carcinoma and non-Hodgkin's lymphoma was observed.[3] The follow-up period for non cutaneous cancers was

10.7 years. The researchers suggest that

these results may have occurred by chance. Further studies are needed to confirm this finding.

Minimising the risk In order to reduce the risk of skin carcinomas a number of strategies have been suggested (see table 2). One of the most important of these is the recommendation that

<200 treatments ofPUVA are administered) I] This advice is based on the general consensus that non-melanoma

skin cancer is increased with

>200 treatmentsp] and

that the greatest risk of malignant melanoma occurs in patients who have received ~250 doses.[3]

References I. Lindeliif B. Risk of melanoma with psoralenlultraviolet A therapy for psoriasis. Do the known risks now outweigh the benefits? Drug Safety 1999; 20 (4): 289-97 2. Stern RS. Nichols KT, Vakeva LH. Malignant melanoma in patients treated for psoriasis with methoxsalen (psoralen) and ultraviolet A radiation (PUVA). N Engl J Med 1997; 336 (15): 1041-5 3. Hannuksela-Svahn A, Sigurgeirsson B, Pukkala E, et al. Trioxsalen bath PUVA did not increase the risk of squamous cell skin carcinoma and cutaneous malignant melanoma in a joint analysis of 944 Swedish and Finnish patients with psoriasis. British J Dermatol 1999; 141: 497-501 4. Drake LA, Ceilly RI, Dorner W, et al. Guidelines of care for phototherapy and photochemotherapy. J Am Acad Dermatol 1994; 31: 643-8 5. Lindeliif B, Sigurgeirsson B, Tegner E, et al. PUVA and cancer: a large-scale epidemiological study. Lancet 1991; 338: 91-3

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