Autologous Bone Marrow Transplantation - Blog Science Connections

562 High-Dose Therapy of CHS Gliomas
20% (15). Our study, therefore, was historically controlled and was designed
to be able to detect a 40% 2-year survival rate. The dose chosen for
administration was less than the maximal dose to avoid a substantial degree
of pulmonary toxicity. Eighteen patients were treated with early promising
results. However, pulmonary toxicity and late relapses resulted in a survival
rate that was not statistically different from that of standard therapy. As in the
phase II carmustine study, nonmyeloid toxicity was severe, including four
episodes of fatal pulmonary toxicity and two additional patients who had
severe toxicity that responded to corticosteroid therapy. Although high-dose
carmustine had a high response rate in patients with progressive gliomas, the
magnitude of tumor reduction was insufficient to influence survival when the
drug was administered adjuvantly. However, even though high-dose carmustine
did not produce a benefit in the population as a whole, two patients
are long-term disease-free survivors more than 5 years after diagnosis,
although one patient has developed severe encephalomyelopathy.
The next agent studied was etoposide at a dose of 2400 mg/m 2 . This
agent in standard-dose evaluation had demonstrated modest activity against
CNS tumors (16). Sixteen patients were treated, and only three (19%)
responded, results similar to those of standard-dose therapy. Toxicity of this
therapy was predominantly myelosuppression; mucositis was modest. Two
patients developed fatal infectious complications during the cytopenic
period, but no fatal extramedullary toxicity was noted.
For most tumors, meaningful survival benefit is achieved only when
drugs are administered as synergistic combination chemotherapy. Since
high-dose etoposide is dose-limited by mucositis and does not cause
pulmonary, hepatic, or CNS toxicity, it seemed an ideal agent to combine with
carmustine, which does not cause mucositis and is dose-limited by hepatic
and pulmonary toxicity. Four patients were treated with the combination of
high-dose carmustine and high-dose etoposide. Unfortunately, severe
hepatic toxicity developed in two patients before any patient responded.
Although etoposide at the maximal tolerated dose does not cause severe
hepatic toxicity, large cumulative doses had been associated with that toxicity
(17). This combination produced synergistic toxicity without synergistic
antitumor activity, a possibility of high-dose combination chemotherapy.
One of the requirements of cytotoxic agents anticipated to have activity
against CNS tumors is adequate penetration of the blood-brain barrier.
Thio-TEPA, one of the earliest alkylating agents developed, fulfills this
requirement; it produces drug concentrations in the cerebrospinal fluid
almost equal to that in the serum. Standard-dose thio-TEPA had not been
adequately evaluated against CNS tumors because of imprecise response
criteria and the lack of availability of CT scanning to measure exact tumor
response (18). Presently, only four patients have been treated with high-dose
thio-TEPA with one response noted.
Other studies are now beginning, including an evaluation of high-dose