Assessment of systemic toxicity in children receiving chemotherapy with cyclosporine for sarcoma.
BACKGROUND
Overexpression of P-glycoprotein in malignant tumors has been associated with poor responses to chemotherapy. It appears biologically plausible that addition of the P-glycoprotein inhibitor cyclosporine (CsA) to standard chemotherapy may improve the outcome. The protective functions of P-glycoprotein in healthy tissues, however, have not been fully elucidated. Addition of CsA may lead to increased systemic chemotherapy toxicity, so we compared the rate and severity of chemotherapy-associated systemic toxicity in the presence and absence of CsA.


METHODS
Standard chemotherapy consisted of etoposide/ifosfamide (VP16/IFOS) cycles, alternating with vincristine/dactinomycin/cyclophosphamide (VAC) cycles. CsA was given at a median dose of 20 mg/kg with unaltered doses of the antineoplastic drugs. The analysis of toxicity was performed by comparing clinically significant toxicity events recorded during and after chemotherapy cycles with and without CsA.


RESULTS
Toxicity-related hospital admissions occurred after 93% of VAC cycles with CsA compared to 40% of the cycles without CsA (P < 0. 0001); 29% of VP16/IFOS cycles with CsA led to admissions vs. 12% with non-CsA cycles (P = 0.04). Infections or fever and neutropenia were the main reasons for these admissions. Thirty-seven percent of the VAC cycles with CsA were complicated by culture-proved sepsis, which did not occur in cycles without CsA (P < 0.0001). Requirements for blood and platelet transfusions were greatly increased after VAC cycles with CsA compared to VAC cycles without CsA.


CONCLUSIONS
The chemosensitizer CsA increases the systemic toxicity of VAC chemotherapy in patients with sarcomas. Future trials of chemotherapy with chemosensitizers will have to take into account a potential increase in systemic toxicity. Careful monitoring of chemotherapy-related toxicity becomes mandatory in such studies.
Theis
J G
JG
Division of Clinical Pharmacology and Toxicology, Department of Pediatrics, The Hospital for Sick Children, and Departments of Pediatrics and Pharmacology, The University of Toronto, Toronto, Ontario, Canada.
Chan
H S
HS
Greenberg
M L
ML
Malkin
D
D
Karaskov
V
V
Moncica
I
I
Koren
G
G
Doyle
J
J
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use; D001803:Blood Transfusion; D016009:Chi-Square Distribution; D002648:Child; D002675:Child, Preschool; D003520:Cyclophosphamide / Q000008:administration & dosage; D016572:Cyclosporine / Q000008:administration & dosage / Q000009:adverse effects*; D003609:Dactinomycin / Q000008:administration & dosage; D005047:Etoposide / Q000008:administration & dosage; D005260:Female; D005334:Fever / Q000139:chemically induced; D006801:Humans; D007069:Ifosfamide / Q000008:administration & dosage; D008297:Male; D009503:Neutropenia / Q000139:chemically induced; D010865:Pilot Projects; D017713:Platelet Transfusion; D012189:Retrospective Studies; D012509:Sarcoma / Q000188:drug therapy*; D018805:Sepsis / Q000139:chemically induced; D016896:Treatment Outcome; D014750:Vincristine / Q000008:administration & dosage
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D000972:Antineoplastic Agents, Phytogenic; D003609:Dactinomycin; D014750:Vincristine; D005047:Etoposide; D016572:Cyclosporine; D003520:Cyclophosphamide; D007069:Ifosfamide