The treatment of patients with metastatic
soft tissue sarcomas (STS) is complex. There are limited agents available and many are associated with significant toxicity. When evaluating a patient with metastatic disease, physicians should ask themselves whether there is a role for surgery to render the patient free of disease.
Combination chemotherapy in patients who have not received
chemotherapy in the adjuvant setting is one option, particularly in a young patient with a good performance status. Sequential single-agent
therapy for patients who are more elderly or debilitated by their disease may be more appropriate.
Gemcitabine appears to be an agent with activity, particularly in patients with
leiomyosarcomas. The data regarding prolonged
gemcitabine infusions suggest improved activity that was predicted based on prolonged intracellular
gemcitabine levels. Because of these data, the prolonged infusion schedule should be used. In addition, because of the paucity of effective agents, consideration of clinical trial participation for patients with newly diagnosed metastatic disease is appropriate, particularly in
chemotherapy-insensitive histologies. The role of the newer agents (eg,
ecteinascidin-743,
epothilones, and
mammalian target of rapamycin) is undefined. Ecteinascidin-743 has been the most extensively tested agent, and its ability to slow growth kinetics of a
tumor and stabilize it clinically is intriguing. Data regarding the response to
BMS-247550 will be published shortly and will help define the further role of
epothilones in this disease. There is a preclinical rationale that makes the
mammalian target of rapamycin inhibitors attractive for the treatment of muscle-derived
neoplasms. In addition, there are cell-line data suggesting activity in
rhabdomyosarcoma. These agents are being tested in adult STS and will likely be tested in pediatric histologies when there are more safety data available in that population.
SU11248 will continue to be tested in patients refractory to
imatinib mesylate and may well prove to be another active agent for patients with
gastrointestinal stromal tumors. As depicted by the analysis of
gemcitabine efficacy, agents with activity in a subgroup of STS may be overlooked by the "come one come all" approach to clinical trials in STS. Identifying key targets in specific STS will be helpful in the testing of newer molecularly targeted agents.
Biologic differences will support histology-specific trials to better understand the activity of an agent in a specific disease site or specifically target a
biologic pathway with relevance to the malignant potential of the disease. For future clinical trials in STS to achieve the goal of histology-specific trials, cooperative group and multi-institutional trials will be required to obtain the appropriate patients with these rare histologies. It will also be increasingly important to be committed to obtaining
tumor tissue in these patients to validate hypotheses regarding
tumor biology and the effectiveness of therapeutic agents.