Elise A. Olsen

Phase IIB Multicenter Trial of Vorinostat in Patients With Persistent, Progressive, or Treatment Refractory Cutaneous T-Cell Lymphoma

PURPOSE To evaluate the activity and safety of the histone deacetylase inhibitor vorinostat (suberoylanilide hydroxamic acid) in persistent, progressive, or recurrent mycosis fungoides or Sézary syndrome (MF/SS) cutaneous t-cell lymphoma (CTCL) subtypes. PATIENTS AND METHODS Patients with stage IB-IVA MF/SS were treated with 400 mg of oral vorinostat daily until disease progression or intolerable toxicity in this open-label phase IIb trial (NCT00091559). Patients must have received at least two prior systemic therapies at least one of which included bexarotene unless intolerable. The primary end point was the objective response rate (ORR) measured by the modified severity weighted assessment tool and secondary end points were time to response (TTR), time to progression (TTP), duration of response (DOR), and pruritus relief ( > or = 3-point improvement on a 10-point visual analog scale). Safety and tolerability were also evaluated. RESULTS Seventy-four patients were enrolled, including 61 with at least stage IIB disease. The ORR was 29.7% overall; 29.5% in stage IIB or higher patients. Median TTR in stage IIB or higher patients was 56 days. Median DOR was not reached but estimated to be >or = 185 days (34+ to 441+). Median TTP was 4.9 months overall, and 9.8 months for stage IIB or higher responders. Overall, 32% of patients had pruritus relief. The most common drug-related adverse experiences (AE) were diarrhea (49%), fatigue (46%), nausea (43%), and anorexia (26%); most were grade 2 or lower but those grade 3 or higher included fatigue (5%), pulmonary embolism (5%), thrombocytopenia (5%), and nausea (4%). Eleven patients required dose modification and nine discontinued due to AE. CONCLUSION Oral vorinostat was effective in treatment refractory MF/SS with an acceptable safety profile.

Pivotal Phase III Trial of Two Dose Levels of Denileukin Diftitox for the Treatment of Cutaneous T-Cell Lymphoma

PURPOSE The objective of this phase III study was to determine the efficacy, safety, and pharmacokinetics of denileukin diftitox (DAB389IL-2, Ontak [Ligand Pharmaceuticals Inc, San Diego, CA]) in patients with stage Ib to IVa cutaneous T-cell lymphoma (CTCL) who have previously received other therapeutic interventions. PATIENTS AND METHODS Patients with biopsy-proven CTCL that expressed CD25 on > or = 20% of lymphocytes were assigned to one of two dose levels (9 or 18 microg/kg/d) of denileukin diftitox administered 5 consecutive days every 3 weeks for up to 8 cycles. Patients were monitored for toxicity and clinical efficacy, the latter assessed by changes in disease burden and quality of life measurements. Antibody levels of antidenileukin diftitox and anti-interleukin-2 and serum concentrations of denileukin diftitox were also measured. RESULTS Overall, 30% of the 71 patients with CTCL treated with denileukin diftitox had an objective response (20% partial response; 10% complete response). The response rate and duration of response based on the time of the first dose of study drug for all responders (median of 6.9 months with a range of 2.7 to more than 46.1 months) were not statistically different between the two doses. Adverse events consisted of flu-like symptoms (fever/chills, nausea/vomiting, and myalgias/arthralgias), acute infusion-related events (hypotension, dyspnea, chest pain, and back pain), and a vascular leak syndrome (hypotension, hypoalbuminemia, edema). In addition, 61% of the patients experienced transient elevations of hepatic transaminase levels with 17% grade 3 or 4. Hypoalbuminemia occurred in 79%, including 15% with grade 3 or 4 changes. Tolerability at 9 and 18 microg/kg/d was similar, and there was no evidence of cumulative toxicity. CONCLUSION Denileukin diftitox has been shown to be a useful and important agent in the treatment of patients whose CTCL is persistent or recurrent despite other therapeutic interventions.

A double-blind, vehicle-controlled study evaluating masoprocol cream in the treatment of actinic keratoses on the head and neck

This double-blind, vehicle-controlled, multicenter study evaluated the efficacy and safety of a new topical antineoplastic agent, masoprocol, in the treatment of actinic keratoses of the head and neck. Of the 113 patients who applied topical masoprocol twice a day for 14 to 28 days, there was a mean decrease in actinic keratoses from 15.0 to 5.4 and a median percent reduction from baseline actinic keratosis count of 71.4% at the 1-month follow-up visit. Comparable numbers for the vehicle-treated group were 13.4 to 11.1 actinic keratoses and 4.3% median percent reduction. Irritation, as manifested by erythema or flaking, occurred in 61.5% of topical masoprocol-treated patients versus 26.7% of those treated with vehicle and did not correlate with clinical response. Topical masoprocol appears to be useful in the treatment of actinic keratoses.

EORTC, ISCL, and USCLC consensus recommendations for the treatment of primary cutaneous CD30-positive lymphoproliferative disorders: lymphomatoid papulosis and primary cutaneous anaplastic large-cell lymphoma

Primary cutaneous CD30(+) lymphoproliferative disorders (CD30(+) LPDs) are the second most common form of cutaneous T-cell lymphomas and include lymphomatoid papulosis and primary cutaneous anaplastic large-cell lymphoma. Despite the anaplastic cytomorphology of tumor cells that suggest an aggressive course, CD30(+) LPDs are characterized by an excellent prognosis. Although a broad spectrum of therapeutic strategies has been reported, these have been limited mostly to small retrospective cohort series or case reports, and only very few prospective controlled or multicenter studies have been performed, which results in a low level of evidence for most therapies. The response rates to treatment, recurrence rates, and outcome have not been analyzed in a systematic review. Moreover, international guidelines for staging and treatment of CD30(+) LPDs have not yet been presented. Based on a literature analysis and discussions, recommendations were elaborated by a multidisciplinary expert panel of the Cutaneous Lymphoma Task Force of the European Organization for Research and Treatment of Cancer, the International Society for Cutaneous Lymphomas, and the United States Cutaneous Lymphoma Consortium. The recommendations represent the state-of-the-art management of CD30(+) LPDs and include definitions for clinical endpoints as well as response criteria for future clinical trials in CD30(+) LPDs.

Interferon alfa-2a in the treatment of cutaneous T cell lymphoma*

Twenty-two patients with Stages Ia to IVa cutaneous T cell lymphoma were entered into a controlled trial of interferon alfa-2a (Roferon-A). Patients initially received either 3 million IU interferon alfa-2a, or their dosage was escalated to 36 million IU intramuscularly daily for a 10-week induction period. At the end of induction, 14/22 (64%) of patients had an objective antitumor response: three patients had a complete response, ten patients had a partial response (greater than or equal to 50% resolution of clinical disease), and one patient had a minor response. Responders included those with Stages Ia to IVa cutaneous T cell lymphoma, and remissions have lasted at least 4 to 27.5 months. Three patients progressed from a partial to complete response with further treatment, for an overall complete response rate of 27%. Acute flu-like side effects were generally minor and transient. Malaise/fatigue, depression, anorexia, and weight loss were common chronic dose-related side effects and the most frequent reasons for dose reduction or discontinuation of drug. Leukopenia was the most common laboratory side effect and was also dose-related. Recombinant human leukocyte interferon alfa-2a is an effective and well-tolerated single-agent therapy for early and advanced cutaneous T cell lymphoma.

Alopecia areata investigational assessment guidelines

From Duke University Medical Center, Durhama; University of Minnesota, Minneapolisb; Pontefract General Infirmaryc; University of California at San Franciscod; Northwest Cutaneous Research Specialists, Portlande; The University of British Columbia, Vancouverf; and Johnson & Johnson, Skin Biology Research Center, Skillman.g Reprint requests: Elise A. Olsen, MD, Professor of Medicine, Duke University Medical Center, Box 3294, Durham, NC 27710. J Am Acad Dermatol 1999;40:242-6. *Developed from the Alopecia Areata Consensus meeting sponsored by the National Alopecia Areata Foundation at the First Tricontinental Meeting of the Hair Research Societies, Brussels, Belgium, Oct 8, 1995. Participants are listed at the end of the guidelines. Copyright

Methods of hair removal

The invention features a method of removing a hair, involving mechanically or chemically removing the hair to expose the follicle of the hair, and then treating the follicle to inhibit its ability to regenerate a hair. Removing the hair facilitates the uptake of a follicle-inactivating compound and thus allows for long-term inhibition of hair growth.

Tretinoin emollient cream: a new therapy for photodamaged skin.

BACKGROUND Tretinoin administered topically in 0.1% concentration has been shown to improve the wrinkling and irregular pigmentation of photoaged skin. OBJECTIVE The purpose of this study was to assess the safety and efficacy of various concentrations of tretinoin in a new emollient cream base in the treatment of photoaged skin. METHODS Three concentrations of tretinoin (0.05%, 0.01%, and 0.001%) in a new emollient cream formulation were compared with vehicle in a 24-week, double-blind, randomized, multicenter study of 296 subjects with photodamaged facial skin. RESULTS Tretinoin emollient cream 0.05% gave a significantly better global response to therapy than vehicle (p less than 0.001), with 68% of subjects exhibiting improvement at the end of therapy, compared with 43% of subjects in the vehicle group. An excellent or good response was found in 26% of subjects treated with tretinoin emollient cream 0.05% versus 11% of vehicle-treated subjects. Fine wrinkling, mottled hyperpigmentation, and roughness were more improved in subjects who received tretinoin emollient cream 0.05% than in vehicle-treated subjects (p less than 0.05). No significant difference was found between vehicle and tretinoin emollient cream 0.01% or 0.001%. Histologic examination showed increases in epidermal and granular layer thickness, decreased melanin content and compaction of the stratum corneum after therapy with tretinoin emollient cream 0.05% or 0.01%. Mild to moderate skin reactions, such as erythema, peeling, and burning, were the most common side effects and, although most prevalent in the group using the 0.05% concentration, generally did not limit tretinoin use. CONCLUSION Tretinoin emollient cream 0.05% appears to be safe and effective in the treatment of photodamaged skin.

The pharmacology of methotrexate.

Methotrexate is a useful antimetabolite for the treatment of both benign and malignant proliferative disorders. When the pharmacokinetics and potential toxicity of this drug are understood, treatment regimens can be tailored to the underlying kinetics of the target population. With the appropriate knowledge of the importance of urinary excretion of methotrexate and factors that influence this and with the ready availability of leucovorin, toxicity can be avoided in all but the most unusual of circumstances.

A proposed EGFR inhibitor dermatologic adverse event-specific grading scale from the MASCC skin toxicity study group

BackgroundAccurate grading of dermatologic adverse events (AE) due to epidermal growth factor receptor (EGFR) inhibitors (EGFRIs) is necessary for drug toxicity determinations, interagent comparisons, and supportive care trials. The most widely used severity grading scale, the National Cancer Institute’s Common Terminology Criteria for Adverse Events version 4.0 (NCI-CTCAE v4.0), was not designed specifically for this class of agents and may result in underreporting and poor grading of distinctive adverse events. We believe a class-specific grading scale is needed to help standardize assessment and improve reporting of EGFRI-associated dermatologic AEs.MethodsThe Multinational Association of Supportive Care in Cancer (MASCC) Skin Toxicity Study Group conducted an international multidisciplinary meeting that included 20 clinicians and researchers from academic centers and government agencies. Experts from different disciplines presented current information specific to EGFRI-induced dermatologic toxicities: grading scale development, pharmacovigilance safety reporting, health-related quality of life, patient reporting, and pharmacology. Group discussions, literature reviews, and professional expertise established the theoretical foundation for the proposed grading scale.ResultsA new grading system is proposed for the most common events associated with EGFRI-induced dermatologic AEs: papulopustular reaction or acneiform rash, nail changes, erythema, pruritus, xerosis, hair changes, telangiectasias, hyperpigmentation, mucositis, flushing, radiation dermatitis, hyposalivation, and taste changes. The proposed scale maintains consistency with the grading principles and language of the existing CTCAE version 4.0 and MedDRA terminology and includes relevant patient-reported health-related quality of life factors.ConclusionsA grading scale specific to EGFR inhibitor dermatologic AEs is presented for formal integration into future versions of CTCAE and for validation in clinical trial settings. The study group designed this scale to detect and report EGFRI-related toxicities with greater sensitivity, specificity, and range than the scales currently used. This scale should serve as a foundation for efforts to perform objective interdrug comparisons and assessments of supportive care treatment strategies more effectively than with current methods.