Phase I trial of dacarbazine with cyclophosphamide, carmustine, etoposide, and autologous stem-cell transplantation in patients with lymphoma and multiple myeloma.
OBJECTIVE
We investigated the feasibility of escalating doses of dacarbazine (DTIC) in combination with high-dose cyclophosphamide, carmustine, and etoposide (CBV) given with autologous stem-cell transplantation in 33 patients with relapsed or refractory lymphoma or multiple myeloma.


METHODS
Eligible patients were treated in this phase I study with cyclophosphamide (7.2 g/m2), carmustine (BCNU) (600 mg/m2), etoposide (2.4 g/m2), and escalating doses of DTIC (3,000 to 6,591 mg/m2) administered either as a 2- (in 23 patients) or a 6- (in 10 patients) hour infusion to determine the maximum-tolerated dose (MTD) of DTIC and the toxicity profile of this combination.


RESULTS
The MTD of DTIC infused over 2 hours and given with the CBV regimen was 3,900 mg/m2, with the dose-limiting toxicity being hypotension. Seven patients experienced transient acute hypocalcemia in association with the DTIC infusion. Prolonging the DTIC infusion to 6 hours or administration of supplemental calcium did not allow further dose escalation of DTIC to occur. Other non-hematologic toxicities observed with this regimen have been reported with CBV alone. Of 25 patients assessable for tumor response at first evaluation posttransplant, 13 (52%) were in complete remission (CR), four (16%) were in partial remission (PR), five (20%) had stable disease (SD), and three (12%) had progressive disease (PROG). Of 31 patients assessable for relapse-free survival, 22 are alive with 13 in CR, one in PR, two with SD, and six with PROG at a median follow-up duration of 313 days (range, 35 to 749+). Treatment-related mortality occurred in six patients (18%).


CONCLUSIONS
The feasibility of combining DTIC in high doses with the CBV regimen has been demonstrated. Dose-limiting hypotension is transient and reversible when DTIC is administered at 3,900 mg/m2 with CBV. Future trials to evaluate the effect of the addition of DTIC to the CBV regimen on response rate and relapse-free survival are encouraged.
Adkins
D R
DR
University of Texas Health Science Center at San Antonio.
Salzman
D
D
Boldt
D
D
Kuhn
J
J
Irvin
R
R
Roodman
G D
GD
Lyons
R
R
Smith
L
L
Freytes
C O
CO
LeMaistre
C F
CF
D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002330:Carmustine / Q000008:administration & dosage / Q000009:adverse effects; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000009:adverse effects; D003606:Dacarbazine / Q000008:administration & dosage / Q000009:adverse effects; D005047:Etoposide / Q000008:administration & dosage / Q000009:adverse effects; D005240:Feasibility Studies; D005260:Female; D005500:Follow-Up Studies; D018380:Hematopoietic Stem Cell Transplantation; D006689:Hodgkin Disease / Q000628:therapy; D006801:Humans; D006996:Hypocalcemia / Q000139:chemically induced; D007022:Hypotension / Q000139:chemically induced; D008223:Lymphoma / Q000628:therapy*; D008228:Lymphoma, Non-Hodgkin / Q000628:therapy; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000628:therapy*; D012074:Remission Induction; D014182:Transplantation, Autologous
D005047:Etoposide; D003606:Dacarbazine; D003520:Cyclophosphamide; D002330:Carmustine