Autologous Bone Marrow Transplantation - Blog Science Connections

High-Dose Therapy and ABMT in Breast Cancer 483
TEPA. Larger ratios of thio-TEPA to cyclophosphamide resulted in unacceptable
toxicity (Dan Griswald, 1986; personal communication).
In the clinic cyclophosphamide as a single agent can be given at 7.5
g/m 2
without ABMT support with dose-limiting perimyocarditis. Thio-TEPA
(1500 mg/m 2 ) as a single agent with ABMT resulted in dose-limiting
neurotoxicity and mucositis (8; unpublished data).
Thus, cyclophosphamide and thio-TEPA in combination appear to be
synergistic in the laboratory setting. Both are active at standard doses in
breast cancer. The MTDs for both agents are established with and without
autotransplant and the organ toxicities at high doses are nonoverlapping—
myopericarditis for cyclophosphamide and neurotoxicity and mucositis for
thio-TEPA.
Our current regimen (STAMP III) combines cyclophosphamide at 6
g/m 2
with escalating doses of thio-TEPA. In 20 patients with various tumors,
there has been one death owed to infection at the second dose level (360
mg/m 2
of thio-TEPA). Diarrhea, rash, and mucositis appear dose related and
become dose limiting at 900 mg/m 2
of thio-TEPA.
Response occurred in one of three patients with breast cancer treated at
thio-TEPA doses less than 400 mg/m 2
and five of five patients treated at
doses greater than 400 mg/m 2 . Pharmacokinetic studies of thio-TEPA for
the 4-day continuous infusion revealed two-fold variations in the area under
the curve among the patients at each dose level. Thio-TEPA levels during the
infusion for the 180,500, and 900 mg/m 2
dose levels have been 0.7,1.9, and
5 urn, respectively.
We have begun a study of four cycles of induction with continuous
infusion high-dose doxorubicin, methotrexate, and 5-fluorouracil, followed by
intensification with cyclophosphamide and thio-TEPA in patients with untreated
stage IV breast cancer.
ACKNOWLEDGMENTS
This work was supported by National Cancer Institute grants
PO1CA3849301A1 and CA0516 and Research Training Fellowship, respectively.
W. David Henner is a Leukemia Society Scholar. Dr. J. P. Eder is a
recipient of the ACS Career Development Award. Dr. A. Elias is an American
Cancer Society Physicians Research Training Fellow.
We are grateful to Ms Beth Doucette for the preparation of this
manuscript.
REFERENCES
1. Anderson KC, Nadler LM. In Important Advances in Oncology, DeVita VT Jr, Hellman S,
Rosenberg SA, eds. J. B. Lippincott, New York, 1986.
2. Antman K, Eder JP, Frei III E. In Important Advances in Oncology, DeVita V, Hellman S,
Rosenberg S, eds. J. B. Lippincott, New York (in
press).