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No benefit to increasing dose intensity of chemotherapy in osteosarcoma, study finds

January 17, 2007

A dose-intensive regimen of the chemotherapy drugs cisplatin and doxorubicin offered no clinical benefit over standard doses of the chemotherapy drugs in patients with a bone cancer called osteosarcoma, according to results from a randomized trial in the January 17 issue of the Journal of the National Cancer Institute. Although the dose-intensive regimen killed tumor cells better than the standard regimen after surgery, survival rates were similar in both groups.

Some studies in cancers such as non-Hodgkin lymphoma and breast cancer have suggested that increasing the intensity of a chemotherapy regimen—that is, decreasing the number of days between chemotherapy treatments—may improve survival. Because chemotherapy drugs can be very toxic, doctors often have to add additional medications to such dose-intense regimens so the patient can tolerate them. For example, some chemotherapy drugs cause a patient's white blood cell count to drop, so doctors also give patients a drug called granulocyte colony-stimulating factor (G-CSF) to increase their production of white blood cells.

In the new study, Ian J. Lewis, M.D., of St. James University Hospital in Leeds, England, with colleagues at the Medical Research Council Clinical Trials Unit in London and the European Osteosarcoma Intergroup, tested whether a dose-intensive regimen consisting of standard drugs used to treat osteosarcoma would improve survival when given before surgery to remove the tumor. A total of 497 patients age 40 or younger with high-grade osteosarcoma that had not spread elsewhere in the body were randomly assigned to receive six cisplatin-doxorubicin treatments at 3-week intervals (standard regimen) or to receive the treatments at 2-week intervals (dose-intense regimen). The patients receiving the dose-intense regimen also received injections of G-CSF to help them better tolerate the chemotherapy.

The researchers observed favorable tumor responses—measured by tumor cell death—in 36 percent of patients receiving the standard treatment and in 50 percent of those receiving the dose-intense regimen. However, after an average of about 5 years, overall survival and progression-free survival were similar in both groups; for example, overall survival was 55 percent in the conventional-treatment group and 58 percent in the dose-intense group. Those who received the dose-intense regimen had a lower risk of leukopenia (low white cell count) and neutropenia (low neutrophil count) but a higher risk of thrombocytopenia (platelet deficiency) and mucositis (inflamed mucus membranes).

"[The dose-intense regimen] resulted in more tumors having good histologic response to preoperative chemotherapy, but this did not translate into a demonstratable patient benefit in overall survival or progression-free survival over [the conventional regimen]," the authors write. "This emphasis placed on histologic response as the key treatment-related predictive factor is thereby challenged."

Indeed, writes editorialist Stephen L. George, Ph.D., of Duke University Medical Center, "promising early results measured by response rates often do not translate into long-term benefits such as longer progression-free survival or overall survival." Part of the reason for this, he writes, is that large increases in response rates are needed to translate into measurable differences in survival. George reviews the conditions under which response rate is a useful endpoint, and notes that this osteosarcoma clinical trial doesn't meet those circumstances. "It is clear that response rate as an endpoint is most useful in early phase clinical trials, in which interest focuses more on assessing activity than proving clinical benefit, and as an important but secondary outcome in more definitive trials," he writes.

Journal of the National Cancer Institute