Capecitabine

Abstract

Bryostatin-1 is a new chemotherapeutic agent that inhibits protein kinase C. The most common side effect and the dose limiting toxicity is myalgia. The cutaneous side effects reported during the phase I and II trials were alopecia, mucositis, nonspecific "rash," "bronzing," and hyperpigmentation in sun exposed areas. No specific acute drug eruptions have been reported. We present the first reported case of a morbilliform drug eruption with histologic features of intraepidermal and subcorneal spongiotic pustules containing eosinophils secondary to bryostatin-1.

Introduction

Bryostatin-1 is one of several new antineoplastic agents targeting protein kinase C. Use of the drug in cancer therapy remains under investigation in Phase II clinical trials. Thus far, the evidence indicates it has little efficacy as a single agent but has promise in combination with cytotoxic agents or in sequence with other signal transduction modulators (1,2).

Bryostatin-1 has been tested in patients with a wide variety of cancers, including but not limited to renal cell adenocarcinoma, melanoma, chronic myelocytic leukemia, chronic lymphocytic leukemia, multiple myeloma, non-Hodgkin's lymphoma, colorectal cancer, sarcoma of the head and neck, and squamous cell carcinoma of the head and neck. To date, three published Phase II trials report cutaneous side effects to treatment with bryostatin-1 (3-6). Included in these studies are 21 cases of a nonspecific "rash," one case of clearing of psoriasis, two cases of "bronzing," and one case of hyperpigmentation in sun exposed areas. No acute drug eruptions have been reported and the clinical presentation of the previous dermatoses are unclear (3-5).

Case Report

A 50-year-old white male with metastatic gastric adenocarcinoma was started in June of 2002 on weekly paclitaxel with bryostatin on the next day. He had no known drug allergies. On the first night of bryostatin administration the patient developed severe itching followed by an erythematous eruption and fever. Laboratory studies in the emergency room revealed normal liver function tests and a complete blood count with a differential of 84% neutrophils and 6% eosinophils. He was treated with methylprednisolone sodium succinate 125 mg IM, cetirizine HCl 10 mg po QD, famotidine 40 mg po QD, and a 5 day tapering course of oral methylprednisolone starting at 28 mg. He also used oatmeal baths and topical calamine lotion. The patient did not improve and was referred to dermatology.

On physical exam he had a symmetrical, non-blanching, bright red, morbilliform eruption resembling a capillaritis rash over his feet, thighs, elbows, and buttocks (Figure 1). There was sparing of the popliteal fossa and a sharp cut-off above the buttocks. Multiple dysplastic appearing nevi were present on the lower back and sacrum. All mucosal surfaces were intact. A punch biopsy specimen taken from the left anterior thigh revealed basket-weave orthokeratosis and underlying epidermal eosinophilic spongiosis with spongiotic pustules in the upper stratum malpighii and subcorneal locations (Figure 2A). In addition, there was a superficial and deep perivascular infiltrate of mononuclear cells and eosinophils (Figure 2B). These findings were consistent with a reaction to an internal antigen such as a drug. Fungal stains were not performed; however, tissue cultures for both bacteria and fungi were negative.

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The patient was placed on triamcinolone 0.1% cream twice daily, doxepin 10 mg by mouth once daily, and continued on the cetirizine HCL and oatmeal baths. The bryostatin was discontinued and the patient continued receiving paclitaxel. The drug eruption resolved in approximately five days. The patient was then started on capecitabine along with paclitaxel, and had no recurrence of his rash.

Discussion

The bryostatins are macrocyclic lactones isolated from the marine bryozoan Bugal neritina (2,7). Bryostatin-1 is a chemotherapeutic agent that has biologic activity as a potent inhibitor of protein kinase C, and may act as a partial agonist or a pure antagonist depending on the tissue (1,7). It also demonstrates activity in induction of interleukin-lb, interleukin-6, interleukin-8, and tumor necrosis factoralpha (TNF-a). The drug's primary role in chemotherapy is through alteration of signal transduction by down regulation of protein kinase C (1,2,7).

Bryostatin-1 was introduced into Phase I trials in 1993 and is currently in Phase II clinical trials. Various dosing regimens have been evaluated and in each study the dose-limiting toxicity is myalgia (1,2). In a review of the literature, other commonly reported side effects include: fatigue, hematologic abnormalities, gastrointestinal symptoms, arthralgia, and headache (3-6, 8-15). A complete list of side effects observed during Phase I and II trials with bryostatin-1 are included in Table I.

In two studies with a combined total of 77 patients, there were 20 patients with a "rash" but no details as to the pattern or extent of the eruption (3,5). In a separate study of 30 patients, three out of seven patients who received greater than six months of treatment developed skin changes: two with generalized "bronzing of the skin," and one with mild hyperpigmentation in sun exposed areas which was labeled as dermatitis (4).

Other drugs reported to cause pustular reactions include [beta]-lactam antibiotics, cephalosporins, quinolones, tetracyclines, protease inhibitors, calcium channel blockers, and nonsteroidal anti-inflammatory agents (16). To our knowledge this is the first report of an acute morbilliform eruption with histologic features of pustular dermatosis secondary to bryostatin-1. It is possible that the ability of bryostatin to induce interleukin-8 may be responsible for pustulosis in the skin. Although it is early in the course of this new drug, we believe this is the first acute drug reaction as a result of bryostatin-1. With further studies more cutaneous manifestations are likely to present.

References

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ADDRESS FOR CORRESPONDENCE:

Madeleine A Duvic MD

Department of Dermatology

1515 Holcombe Blvd, Box 0434

Houston, TX 77030

T: 713-745-1113

F: 713-745-3594

E: mduvic@mdanderson.org

JENNIFER M KREJCI-MANWARING MD, MELISSA A BOGLE MD HAFEEZ A DIWAN MD, AND MADELEINE A DUVIC MD

DEPARTMENTS OF DERMATOLOGY (1) AND PATHOLOGY (2) UNIVERSITY OF TEXAS M.D. ANDERSON CANCER CENTER HOUSTON, TEXAS

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