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Thalidomide in Hematologic and Oncologic Disease

Thalidomide in Hematologic and Oncologic Disease

Introduction

The use of thalidomide (Thalomid) in the treatment of hematologic diseases and in solid tumors as monotherapy or in combination with other agents is an exciting development in cancer therapy. Researchers actively involved in studying the role of thalidomide in cancer treatment were convened at a special investigators’ meeting held this past May in New Orleans. The articles in this supplement are based on the presentations made at this investigators’ meeting.

The clinical utility of thalidomide has grown significantly over the past 2 to 3 years, and at the present time, there are over 100 different studies underway using thalidomide in about 40 different illnesses. The clinical uses of thalidomide can be loosely associated with a number of biological or cellular activities. In particular, modulation of tumor necrosis factor-alpha (TNF-alpha) inhibition, antiangiogenic properties, and stimulation of the immune system have been reported to be responsible for these positive clinical activities.

Thalidomide was developed as a sedative back in the 1950s and became popular when sold as an over-the-counter product in Europe and Canada. Shortly thereafter, however, negative effects of the drug started to appear with chronic use. In particular, these included peripheral neuropathy, now a familiar side effect of thalidomide, and teratogenicity, which ultimately was responsible for the drug being taken off the market.

It was not until the early 1990s that researchers at Rockefeller University identified thalidomide as an inhibitor of TNF-alpha, and soon thereafter, reports of thalidomide’s antiangiogenic properties were also made. It has only been within the past 2 years that encouraging results have emerged with the use of thalidomide in cancer, and in particular, multiple myeloma.

Clinical Trials of Thalidomide

The articles in this supplement will discuss the status of several ongoing clinical trials of thalidomide. Studies at the University of Arkansas, the Mayo Clinic, and several other institutions worldwide are evaluating the role of single-agent thalidomide in the treatment of multiple myeloma. Although its mechanism of action in myeloma is still not clear, thalidomide appears to be active in some patients with refractory myeloma. This is discussed further in my article entitled "Thalidomide in Multiple Myeloma." Investigators at the Royal Marsden Hospital and University College in London have studied thalidomide both as low-dose (100 mg orally, every night) and high-dose (600 mg, given as 300 mg, twice daily) therapy for patients with a variety of solid tumors. Dr. Timothy Eisen presents a report on these studies in his article "Thalidomide in Solid Tumors."

Clinical experience with thalidomide has also included observation of improvement in patients with prostate cancer and apparent responses in patients with metastatic disease refractory to chemotherapy. Dr. Danai Daliani and colleagues have initiated a study of neoadjuvant thalidomide treatment in patients with locally advanced prostate cancer. They have also initiated a phase I/II trial of thalidomide, paclitaxel (Taxol), and estramustine (Emcyt) treatment in patients with metastatic androgen-independent prostate cancer who may have failed on up to two courses of chemotherapy. These are discussed further in Dr. Daliani’s article "Development of Angiogenesis Inhibition as Therapy for Prostate Cancer."

A combination of thalidomide and temozolomide is currently being investigated in a phase I/II study in metastatic melanoma. This is discussed further in Dr. Wen-Jen Hwu’s article "New Approaches in the Treatment of Metastatic Melanoma: Thalidomide and Temozolomide." In Dr. Rangaswamy Govindarajan’s article "Irinotecan and Thalidomide in Metastatic Colorectal Cancer," the author discusses an ongoing phase II protocol using this regimen and has noted a remarkable absence of grade 3/4 gastrointestinal toxicities. The author concludes that further testing of this regimen is warranted.

Finally, in a pilot study performed at The University of Texas M. D. Anderson Cancer Center, investigators looked to determine the feasibility of using thalidomide in a population of renal-cell carcinoma patients with progressive disease, despite chemotherapy and immunotherapy. Dr. Robert Amato presents a case report of one patient in this pilot trial in his article "Thalidomide for Recurrent Renal-Cell Cancer in a 40-Year-Old Man."

 
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