Drug combination offers promise in treating resistant bone cancer

A new combination of two anti-cancer drugs offers promise in treating recurrent and treatment-resistant bone cancer in children, according to a study conducted by researchers at St. Jude and Rady Children’s Hospital at the University of California at San Diego.

The study, reported in the advance online issue of the journal Cancer, is the first to analyze the effectiveness of the combination of the anti-cancer drugs gemcitabine and docetaxel in treating bone sarcomas that relapsed or had not responded to other treatments in children. The study found that the drug combination showed an anti-tumor response in about 30 percent of the 22 young sarcoma patients who received the drugs, and that the toxicity was manageable. The responses were seen in two types of bone sarcomas: osteosarcoma and malignant fibrous histiocytoma (MFH). Sarcomas are malignant tumors that affect bone, muscle and connective tissue.

Najat Daw, MD, Oncology, said the finding, although preliminary, offers an important, new avenue for treating drug-resistant sarcomas. Daw is the paper’s senior author.

“A major issue we face in managing patients with recurrent sarcomas is the paucity of active agents,” Daw said. “There is a limited number of drugs that are active against bone sarcomas, and these are usually used as front-line treatments. When the sarcomas recur, we have essentially no active agents.”

An advantage of the gemcitabine-docetaxel combination is that each drug attacks cancers in a different way, Daw said. Gemcitabine is a molecular mimic of one of the building blocks of DNA. It interferes with the DNA synthesis critical for the rapid growth of cancer cells. Docetaxel jams the machinery of cell division that cancer cells need to proliferate. Besides their complementary mechanisms of action, the drugs show somewhat different type of toxicity, meaning that the combination is not likely to produce additive toxicity effects, Daw said.

The researchers were prompted to test the drug combination in pediatric patients by other studies in adults showing it was effective in treating sarcomas.

“We were first very careful to see whether we would see any excess toxicity in children compared to that seen in adults,” Daw said. “When we found that the combination was well tolerated, we used it in more patients. Since our colleagues at Rady Children’s Hospital were also using it for refractory sarcoma, we decided to pool our data.”

According to Daw, the 30 percent response rate is promising given that the drug combination represents the only treatment that has shown any effectiveness against treatment-resistant osteosarcoma or MFH.

Daw added that the new study was a retrospective analysis of patient records rather than a rigorous prospective clinical trial. Thus, the researchers concluded that “Further evaluation of this drug combination is warranted in these patients.”

Besides conducting such a prospective study of the drugs, another research direction would be to test the two drugs in combination with new, targeted anti-cancer drugs that are being developed, Daw said. Gemcitabine and docetaxel are broadly toxic to any proliferating cells—affecting cancer cells more because they are more actively proliferating. However, the new targeted drugs specifically inhibit a component of the cell’s machinery that is active only in cancer cells, Daw said.

(Source: Cancer: St Jude and Rady Children’s Hospital at the University of California at San Diego: June 2008)