Current treatment of Cutaneous T-Cell Lymphoma.

Cutaneous T-cell lymphomas are a heterogeneous group of cutaneous non-Hodgkin's lymphomas. In the United States, the incidence of these diseases is rising faster than any other cancer. Environmental triggers may be important in the evolution of malignancy. Current therapy is reviewed with emphasis on a new retinoid, Targretin.

Innovative treatment approaches for rheumatoid arthritis. Cyclosporin, leflunomide and nitrogen mustard.

Cyclosporin A (CSA) Cyclosporin inhibits IL-2 release and T-cell activation and, secondarily, affects B-cell function. It also inhibits bone resorption, at least in vitro. This drug's bio-availability averages 25-35% but is highly variable. Food and grapefruit juice enhance bio-availability and newer formulations may make its absorption more reliable. It is highly concentrated in fatty tissues and red blood cells but does not cross the blood-brain barrier. CSA is metabolized to numerous metabolites by the liver and its elimination half-life is 6-12 hours in the absence of severe liver disease. Biliary excretion accounts for 94% of CSAs elimination. Because it is highly metabolized, its metabolism can be inhibited by other drugs (e.g. ketoconazole and erythromycin) or its metabolism can be induced (e.g. anticonvulsants). Cyclosporin is more effective than placebo for the treatment of rheumatoid arthritis and as effective as other antirheumatics. There is potential for the use of CSAs in DMARD combinations. The principal toxicities of cyclosporin are gastro-intestinal and renal, with the latter being of more concern. Leflunomide (LF). Leflunomide may be a pyrimidine synthesis inhibitor, although tyrosine kinase inhibitor may also be part of its mechanism of action. Its active metabolite is excreted renally to a large degree, with a prolonged elimination half-life of about 11 days. Since LF is activated by liver metabolism, renal failure may have less effect on kinetics than severe liver disease. Early data on efficacy indicate efficacy at 10-25 mg/day, although more well-controlled data is necessary. Toxicity relates to the skin, liver and GI tract, although some degree of weight loss was also found. Nitrogen mustard (NM). Nitrogen mustard is an alkylating agent whose pharmacokinetics are poorly understood. Small, open studies in RA indicate that NM has a potential for relatively rapid response (1-2 weeks) but, clearly, much work remains to be done. As an alkylating agent, GI and hematological toxicities are of greatest concern.

Granulocyte colony-stimulating factor (G-CSF) prevents dose-limiting neutropenia in lymphoma patients receiving standard dose chemotherapy.

In this study, nine patients with non-Hodgkin's lymphoma (n = 6) and Hodgkin's disease (n = 3) receiving different cytotoxic chemotherapy regimens were given granulocyte colony-stimulating factor (G-CSF) (5 micrograms/kg/day) from 48 hours after the end of chemotherapy to 48 hours before the next chemotherapy administration. The decrease in mean absolute neutrophil counts (ANC) and in mean platelet (Plt) counts was not significant when pre-therapy counts were compared with post-therapy ones (p < 0.375 and p > 0.4, respectively). The mean actual dose intensity was 92% (range 68-100%). G-CSF treatment after chemotherapy reduces neutropenia and permits administration of the full chemotherapy program. A wash-out period between G-CSF treatment and chemotherapy administration is needed to prevent the detrimental effect of chemotherapy on leukocyte and platelet recovery when repeated cycles of cytotoxic drugs and G-CSF are administered.

Reduced bone mineral density in men following chemotherapy for Hodgkin's disease.

We have measured bone mineral density (BMD) in 29 men, mean age 35.0 (range 19.7-58.0) years, with testicular damage following MVPP or hybrid chemotherapy for Hodgkin's disease. Forearm cortical bone mineral content (BMC) and lumbar spine and femoral neck integral BMD were measured 3.4 (1.1-6.8) years after completion of chemotherapy, and results expressed as Z (standard deviation) scores. There was a significant reduction in forearm cortical BMC (median BMC 1.727 g cm-1, median Z-score -0.8, P < 0.0005), in lumbar spine integral BMD (median BMD 1.141 g cm-2, median Z-score -0.6, P < 0.0005) and in femoral neck integral BMD (median BMD 0.991 g cm-2, median Z-score -0.4, P < 0.05). There was no significant correlation between Z-score and time elapsed since completion of chemotherapy, and no significant difference in Z-score according to type of chemotherapeutic regimen or number of cycles of chemotherapy received. In conclusion, men who are in complete remission following treatment of Hodgkin's disease have reduced cortical and trabecular BMD. Possible causes include mild hypogonadism secondary to chemotherapy-induced impairment of Leydig cell function, a direct effect of chemotherapy on bone, an effect of high-dose glucocorticoid on bone or an effect of Hodgkin's disease per se.

Risk of secondary cutaneous malignancies in patients with long-standing mycosis fungoides.

BACKGROUND: Patients with mycosis fungoides (MF) are frequently treated with UV light and psoralen (PUVA), nitrogen mustard, and electron beam irradiation, modalities known to predispose persons to development of cutaneous malignancies. OBJECTIVE: We assessed the relation between these therapeutic modalities and the development of secondary cutaneous malignancies. METHODS: We reviewed the charts of all patients observed during the past year. RESULTS: We found that 7 of 71 patients had cutaneous neoplasms in an average follow-up time of 8.3 years. Orthovoltage radiation was used in five of seven cases and PUVA in four of seven. Five of seven patients had multiple neoplasms. CONCLUSION: The risk of the development of second malignancies from the treatment of MF is relatively small and appears to be related to the type of therapy.

Eruptive epidermal cysts and multiple squamous cell carcinomas after therapy for cutaneous T-cell lymphoma.

Both topical nitrogen mustard and psoralen photochemotherapy may induce benign and malignant alterations in the skin. We describe the explosive appearance of multiple epidermal cysts and squamous cell carcinomas in a patient whose cutaneous T-cell lymphoma was treated sequentially with these two types of therapy. This is the first report of both processes in the same patient with cutaneous T-cell lymphoma. It strongly supports the concept of lesion induction, while raising the question of an additive or even synergistic effect of these types of therapy.

Cutaneous malignancies and metastatic squamous cell carcinoma following topical therapies for mycosis fungoides.

Specific treatments for mycosis fungoides, including electron beam irradiation, topical mechlorethamine, and psoralen plus ultraviolet A (PUVA) may be associated with the development of skin cancers after a variable latency period. Because these treatments are often not curative, topical therapies for mycosis fungoides, administered sequentially or concomitantly, are being used increasingly in order to control recurrent disease. This report documents the development of multiple cutaneous tumors, including squamous cell carcinoma, basal cell carcinoma, actinic keratoses, keratoacanthomas, and one case of lentigo maligna, in seven patients who received topical therapies for mycosis fungoides. In contrast to the usual latency period between ionizing radiation therapy and the development of skin cancer, two of our patients who had received prior PUVA therapy developed multiple skin tumors upon completion of electron beam irradiation. The development of metastatic squamous cell carcinoma in two of the other seven patients with multiple cutaneous neoplasms suggests that this potential hazard must be considered in the evaluation and treatment of patients with mycosis fungoides.

PUVA therapy prevents sensitization to mechlorethamine in patients with psoriasis.

Two groups of 20 patients with psoriasis were treated with mechlorethamine applied topically (group A) or with PUVA combined with mechlorethamine (group B). In group B mechlorethamine was started after six PUVA treatments. Results showed a significant decrease of the incidence of contact dermatitis in group B (30%) compared with group A (75%). Allergic dermatitis, demonstrated by a positive patch test to mechlorethamine with an histology of eczema, was observed in 55% of patients in group A and 20% in group B. The incidence of irritant dermatitis was not significantly different in the two groups. Allergic dermatitis was observed later in group B: after an average of 32.2 applications of mechlorethamine compared with 25 applications in group A. Possible mechanisms responsible for these results are reduction of epidermal Langerhans cells by PUVA therapy and induction of antigen-specific suppressor T cells. Patients living far from a specialized centre might be treated initially with PUVA therapy then with mechlorethamine alone, at home. This schedule may reduce the incidence of contact dermatitis to mechlorethamine.

Ultraviolet light treatment delays contact sensitization to nitrogen mustard.

Contact sensitivity to nitrogen mustard was delayed after first treating patients with u.v. light. While the number of patients becoming sensitive to nitrogen mustard after ultraviolet light exposure was not significantly different from the control, the number of patients who became sensitive in the first 30 days was significantly less than the control group. It is postulated than this delay in sensitization is due to an alteration of the patients' epidermal Langerhans cells, produced by the u.v. light exposure.

A prospective randomized study of adjuvant parenteral nutrition in the treatment of diffuse lymphoma: effect on drug tolerance.

Total parenteral nutrition (TPN) has been suggested as a useful addition to chemotherapy of malignant disease in the hope of decreasing drug toxicity and increasing drug tolerance. In this study, 17 of 36 patients given chemotherapy for advanced diffuse lymphoma were randomly selected to receive TPN. The dose of the chemotherapeutic agents to be administered was decreased according to predetermined toxicity guidelines. A comparison of drug dosage in the group receiving TPN and the group receiving standard nutrition is a measure of drug tolerance in these patients. Drug dosage was evaluable in 15 TPN and 18 standard nutrition patients. No difference in tolerance of any specific drug or total drug dose occurred when all patients in both groups were compared. Similar comparisons in subgroups of malnourished patients and responding patients also revealed no difference. A cycle-by-cycle analysis demonstrated no difference in any phase of therapy. The wbc count, platelet count, and albumin level, on the first day of each cycle, the nadir during cycles and the day of nadir were compared in TPN and standard nutrition patients. No differences were found. This study does not suggest improved drug tolerance in lymphoma patients as a result of TPN support. Further controlled studies are needed to determine which groups of cancer patients might benefit from TPN and how these benefits occur.

Systemic reactions to topically applied drugs.

Topical drugs can be absorbed percutaneously in sufficient amounts to cause untoward systemic effects. Generally speaking, infants and young children appears to be more vulnerable than adults. It has been shown that the prolonged and extensive use of topical corticosteroids can induce iatrogenic hypercorticism and that they may also impair the patients ability to cope with stress. Furthermore, the relatively limited use, areawise and timewise, of agents such as phenol, resorcinol, salicylic acid, hexachlorophene, boric acid, mercurials, and podophyllin may suffice to elicit dire systemic reactions.