Autologous Bone Marrow Transplantation - Blog Science Connections

482 High-Dose Therapy and ABMT in Breast Cancer
finally, a source of bone marrow stem cells free of clonogenic tumor cells (5).
Patients with breast cancer frequently have bone marrow that is uninvolved by
metastatic tumor. However, ABMT for breast cancer is generally considered
by the clinician only when patients have not responded to multiple regimens.
The solid tumor autologous marrow program (STAMP) Was organized to
integrate an experimental laboratory and clinically based program in the
rational design and systematic evaluation of an effective ablative regimen for
solid tumors based on preclinical observations, pharmacology, and clinical
observations. Alkylating agents were chosen for emphasis in this program
because of their steep dose-response curves, non-cross-resistance, broad
clinical activity, therapeutic synergy, varying nonhematologic toxicity, and
lack of cell-cycle specificity.
The initial study evaluated a combination of cyclophosphamide, cisplatin,
and BCNCI (carmustine) (STAMP I). The maximum tolerated doses (MTDs)
were 5625 mg/m 2 ,165 mg/m 2 , and 600 mg/m 2 , respectively. The toxicity of
the three drugs in the combination was nonoverlapping and, therefore, the
drugs could be combined at almost 100% of the MTD of each agent
individually. Of 17 patients with breast cancer treated on the phases I and II
protocol, 14 were treated at the MTD. Two patients had had no prior
chemotherapy. Two had failed within 6 months of completing adjuvant
chemotherapy and 13 had failed prior chemotherapy. Twelve either had less
than a partial response on initial therapy or progressive disease on secondary
therapy. Of 17 patients, 16 were estrogen receptor protein (ERP) negative. All
were premenopausal. One patient had no measurable disease at the time of
transplant. Of the 16 évaluable patients with breast cancer, 6 responded
completely (38%) and 8 partially (response rate, 88%) (7).
Responses in breast cancer were unusually rapid, with a median of 11
days to partial response (PR) and 12 days to complete response (CR) (7). Five
of six complete responders had met the criteria for a PR by day 7. Because of
the promising results in breast cancer in the STAMP | study, a second
high-dose regimen was designed to combine single agents with known
clinical activity in breast cancer with potentially less toxicity.
Preclinical laboratory studies in MCF7 human breast cancer cells
document a steep dose-response curve for triethylenethiophosphoramide
(thio-TEPA) and 4-hydroperoxycyclophosphamide (4-HC) which can be
measured over 4 logs. When the dose of thio-TEPA was held constant at 10,
50, and 200 jum and the dose of cyclophosphamide increased from 1 to 100
urn, substantial synergy was observed. When the concentration of 4-HC was
constant in three experiments at 5,25, and 50 /Mm and the dose of thio-TEPA
varied from 1 to 200 um, synergy was most impressive at the highest doses of
4-HC.
When mice bearing C3H breast adenocarcinoma were treated with
varying doses of thio-TEPA and cyclophosphamide, survivals were longest
with a 30 mg/kg/day dose of cyclophosphamide and 1 mg/kg/day of thio-