Phase I trial of sequential high-dose chemotherapy with escalating dose paclitaxel, melphalan, and cyclophosphamide, thiotepa, and carboplatin with peripheral blood progenitor support in women with responding metastatic breast cancer.
A single high-dose cycle of chemotherapy with stem cell support can produce disease-free survival of 15-20% for at least 3 years in women with responding stage IV breast cancer. North American Autologous Bone Marrow Transplant Registry data suggest that a complete response (CR) is the single most important prognostic factor associated with prolonged disease-free survival. Therefore, if sequential high-dose chemotherapy can increase the CR rate, then perhaps an increased proportion of patients will remain disease free. Women with at least a partial response (PR) to induction chemotherapy received three separate high-dose cycles of chemotherapy with peripheral blood progenitor support and granulocyte colony-stimulating factor. The first intensification was a dose escalation of paclitaxel (400-825 mg/ m2), the second intensification was melphalan (180 mg/m2), and the third intensification consisted of 6000 mg/m2 cyclophosphamide (1500 mg/m2/day), 500 mg/m2 thiotepa (125 mg/m2/day), and 800 mg/m2 carboplatin (200 mg/m2/day; CTCb). Thirty-six women were enrolled and 31 completed all three cycles. After the paclitaxel infusion most patients developed reversible predominantly sensory neuropathy. Of the 19 patients with measurable disease, 6 converted to CR, 7 converted to a PR* (the complete resolution of all soft tissue or visceral disease with sclerosis of prior lytic bone lesions), and 2 had a further PR for an overall response rate of 79%. Two patients had no further response and disease in two patients progressed, and thus they were taken off the study before CTCb. Seventy-eight percent are progression-free at a median follow-up of 14 months (range, 3-24+). Three sequential cycles of high-dose chemotherapy are feasible and were administered in this study with no mortality. Single agent paclitaxel at doses up to 825 mg/m2 were well tolerated with moderate reversible toxicity.
Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.
L T
LT
Vahdat
K
K
Papadopoulos
C
C
Balmaceda
T
T
McGovern
J
J
Dunleavy
E
E
Kaufman
B
B
Fung
T
T
Garrett
D
D
Savage
A
A
Tiersten
J
J
Ayello
E
E
Bagiella
D
D
Heitjan
K
K
Antman
C
C
Hesdorffer
D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016190:Carboplatin / Q000008:administration & dosage; D003520:Cyclophosphamide / Q000008:administration & dosage; D005260:Female; D019650:Hematopoietic Stem Cell Mobilization; D006801:Humans; D008558:Melphalan / Q000008:administration & dosage; D008875:Middle Aged; D009367:Neoplasm Staging; D009422:Nervous System Diseases / Q000139:chemically induced; D009503:Neutropenia / Q000139:chemically induced; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects; D013852:Thiotepa / Q000008:administration & dosage; D016896:Treatment Outcome
D003520:Cyclophosphamide; D013852:Thiotepa; D016190:Carboplatin; D017239:Paclitaxel; D008558:Melphalan