Multiple cycles of high dose chemotherapy supported by hematopoietic progenitor cells as treatment for patients with advanced malignancies.
BACKGROUND
Retrospective studies suggest that dose intensity is an important determinant of outcome in the treatment of patients with a variety of malignant diseases such as breast cancer, ovarian cancer, and lymphoma. Unfortunately, these results have not been clearly substantiated in prospective randomized trials. One problem with these studies may be that the degree of dose escalation is not sufficient to result in an improved outcome because the chemotherapy doses are limited by hematopoietic toxicity. In an attempt to deliver more dose-intensive therapy, the feasibility of the administration of multiple cycles of high dose chemotherapy with hematopoietic progenitor cell and growth factor support was investigated in patients with advanced malignancies.


METHODS
Nineteen patients with metastatic breast cancer and six patients with refractory non-Hodgkin's lymphoma were initially treated with etoposide (VP-16) (2 gm/m2) and granulocyte-colony stimulating factor (G-CSF). Peripheral blood hematopoietic progenitor cells were collected by leukapheresis and cryopreserved as the patients' leukocyte counts recovered from the nadir induced by VP-16. Patients were then treated with four cycles of mitoxantrone (18 mg/m2), thiotepa (150-200 mg/m2) and cyclophosphamide (4500-5000 mg/m2) as a 48-72 hour continuous infusion followed by infusion of one-quarter of their progenitor cells 48 hours later. All patients also received G-CSF (5 micrograms/kg/day) until engraftment.


RESULTS
A total of 88 of a planned 100 cycles of therapy were administered to these 25 patients. The median time to recovery of an absolute neutrophil count of 500/microliters or greater was 13-14 days (range, 7-18 days) and time to recovery of a platelet count of 20,000/microliters or greater was 13-14 days (range, 7-16 days) after the initiation of each cycle of chemotherapy. The median number of platelet transfusions required after each cycle was 2-3 (range, 0-18 transfusions) and the number of erythrocyte transfusions was 4 (range, 0-10). The most common toxicity was diarrhea. Prophylactic intravenous antibiotics were administered to avoid fever with neutropenia. Two patients developed interstitial pneumonitis and one patient died. One heavily pretreated patient failed to engraft after the first cycle. Reversible veno-occlusive disease of the liver developed in one patient after the fourth cycle of therapy. Four patients progressed while on therapy. Eight patients were disease free and 13 patients had a partial response or had a positive bone scan as the only evidence of disease at the completion of therapy. Seven patients, two with lymphoma and five with breast cancer (28%), remain progression free with a median follow-up of 24.7 months (range, 17-28 months).


CONCLUSIONS
Support with hematopoietic progenitor cells and growth factors allows the timely administration of repetitive cycles of high dose chemotherapy, resulting in a significant increase in dose intensity with acceptable toxicity.
Long
G D
GD
Division of Bone Marrow Transplantation, Stanford University Medical Center, California 94305, USA.
Negrin
R S
RS
Hoyle
C F
CF
Kusnierz-Glaz
C R
CR
Schriber
J R
JR
Blume
K G
KG
Chao
N J
NJ
D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D001803:Blood Transfusion; D001943:Breast Neoplasms / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D003520:Cyclophosphamide / Q000008:administration & dosage; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D005047:Etoposide / Q000627:therapeutic use; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000627:therapeutic use; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007937:Leukapheresis; D008228:Lymphoma, Non-Hodgkin / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D008942:Mitoxantrone / Q000008:administration & dosage; D009362:Neoplasm Metastasis; D013852:Thiotepa / Q000008:administration & dosage
D016179:Granulocyte Colony-Stimulating Factor; D005047:Etoposide; D003520:Cyclophosphamide; D013852:Thiotepa; D008942:Mitoxantrone