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Targeted therapy has been most closely associated with sophisticated monoclonal antibodies or small molecule agents directed at very specific cell surface receptors or intracellular enzymes. However, several chemotherapies may meet definitions of targeted therapy. By acting on very specific cell functions, rather than non-specific cytotoxic effects, such therapies as thalidomide and arsenic trioxide show considerable promise in several solid tumors.

"Thalidomide has found new uses as a tumor anti-angiogenesis agent, and is capable of diminishing the proliferation of angiogenesis-dependent solid malignancies," reported Kenneth B. Ain, MD, during the 20^th annual meeting of the Chemotherapy Foundation. "A putative mechanism relates to the ability of thalidomide to inhibit the processing of some mRNAs, including those of tumor necrosis factor-alpha (TNF-alpha) and vascular endothelial growth factor (VEGF)."

Trials with thalidomide have been wide ranging, with activity reported in thyroid cancers, renal cell carcinoma, and hepatocellular cancer. Studies with arsenic trioxide are more limited but now include several hematologic malignancies and solid tumors, including a phase II trial in refractory prostate cancer. Arsenic trioxide does not appear to affect angiogenesis, but it has been associated with promoting apoptosis.

Thalidomide Trial Data
As a single agent in renal cell carcinoma, thalidomide has now been evaluated in 7 clinical trials. Although no complete responses (CR) were observed in patients treated with thalidomide, most of whom had advanced stage disease, up to 17% had partial response (PR) and up to 64% had stable disease, according to Robert J. Amato, MD, Genitourinary Medical Oncology, Baylor College of Medicine, Houston, Texas.

On the basis of these results, 5 phase II trials have been conducted in which thalidomide was combined with interleukin-2 (IL-2), with gemcitabine and 5-fluorouracil (5-FU) or with interferon-alpha and capecitabine. Both previously treated and treatment-naīve patients were evaluated. Thirty five percent of evaluable patients achieved objective response; a small number of these had complete response.

The most common side effects with thalidomide have been constipation, sedation, rash, and deep vein thrombosis (DVT). The rash is generally manageable but it can be a reason for treatment discontinuation, according to Dr. Amato. He also suggested that DVT, which occurred at rates ranging from 3% to 23%, is a significant concern and may require prophylaxis with an anticoagulant. However, he also emphasized that the considerable level of activity in a difficult disease has been encouraging, despite the side effects. These promising results have prompted the design of a 3-arm phase III trial in which several thalidomide-containing combinations will be compared.

There has also been good evidence of activity with thalidomide in thyroid cancer. In a study that enrolled 26 patients with papillary, follicular, or medullary forms of this malignancy, the response rate in evaluable patients was 50%, with 30% of patients achieving a durable benefit for at least 8 months, according to Dr. Ain. Patient accrual in this trial is continuing and more advanced studies are likely.

In hepatocellular cancer, 31 patients (each with an unresectable nodule of at least 2 cm in size) have been evaluated on a 200 mg daily thalidomide regimen. Approximately 50% had failed a prior chemotherapy regimen. Although 4 patients discontinued therapy due to side effects, there was 1 CR and 1 PR. In addition, 9 patients achieved stable disease, with an average of approximately 5 months before progression.

"The presence of metastases did not appear to influence response with a similar proportion in each group achieving benefit, but a patent main portal vein or inferior vena cava did appear to be important. There was only 1 responder of 13 patients with invasive disease of these vessels versus 10 of 15 (67%) in those with a patent vein," reported Jonathan D. Schwartz, MD, Kaplan Cancer Center, New York University.

The benefits of thalidomide are attributed to its anti-angiogenic effects and possibly to its immunomodulatory properties as well. There is hope that the same effects can be achieved with less toxicity by substituting with thalidomide derivatives. Early experience with these agents suggests that they are more potent than thalidomide but better tolerated, according to Dr. Amato. He reported that phase II trials with the first of these agents, CC4047, are expected early this year.

Arsenic Trioxide: Pilot Results
Pilot results with arsenic trioxide in hormone-refractory prostate cancer have also encouraged further study. Although there was only 1 PR in an initial series of 12 patients, all were heavily pretreated and had advanced disease. Five of the patients had already received palliative radiation therapy for bone metastases.

"The initial results suggest that the activity of arsenic trioxide in hormone-refractory prostate cancer is primarily cytostatic," reported Robert Gallagher, MD, Montefiore Medical Center, Bronx, New York. While he acknowledged that further evidence of benefit is needed before this agent can be moved forward in clinical trials, he noted that it was relatively well tolerated, with fatigue being the most common side effect. However, if arsenic trioxide is to have a role in the treatment of prostate cancer, it is likely to be used in combination with other agents.

The era of targeted therapies has intensified efforts to define rational interventions directed at specific targets of tumor proliferation. While much of the work is being conducted with new compounds with molecular targets, agents such as thalidomide and arsenic trioxide may also provide therapy aimed at critical processes such as angiogenesis. The goal is new and better strategies for improved cancer control.

Key Points In Focus:

The concept of targeted therapy is being expanded to several agents such as thalidomide and arsenic trioxide, based on evidence that they affect such processes as angiogenesis and apoptosis.
Thalidomide has been associated with clinical activity in renal cell carcinoma, thyroid cancer, and hepatocellular carcinoma. Although dose-limiting side effects have been reported with thalidomide, novel analog compounds, which appear to be more potent but better tolerated, may expand the clinical utility of this pathway of cancer inhibition.
Arsenic trioxide has only produced modest activity in a pilot study of hormone-refractory prostate cancer. However, it is an attractive candidate for use in combination therapy, in part because it is relatively well tolerated.

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