A phase I clinical trial of sequentially administered doxorubicin and topotecan in refractory solid tumors.
OBJECTIVE
To determine whether agents that target topoisomerase I and II could be administered sequentially.


METHODS
A Phase I study was conducted to evaluate sequential treatment with bolus IV doxorubicin followed 48 h later by topotecan given as a 30-min i.v. infusion on 3 consecutive days, with additional cycles of therapy repeated every 3 weeks. Characteristics of the 22 patients entered into the study were: 13 male and 9 female; median age, 49.5 (range 33-66) years; Eastern Cooperative Oncology Group performance status, 0-1; and normal cardiac, hematological, hepatic, and renal function. All patients had received prior therapy (median >or=2 prior regimens).


RESULTS
The maximum tolerated dose of the combination was 25 mg/m(2) doxorubicin and 5.25 mg/m(2) topotecan (1.75 mg/m(2)/day x 3). Neutropenia was the dose-limiting toxicity. Attempts to further escalate the dose using 5 microg/kg granulocyte colony-stimulating factor proved unsuccessful because of thrombocytopenia. Among the 17 patients who were evaluable for response, 6 had a partial response, and 4 showed evidence of disease stabilization. The partial responses occurred in patients with small cell lung cancer (3 of 7), non-small cell lung cancer (1 of 6), esophageal adenocarcinoma (1 of 2), and ovarian carcinoma (1 of 1), and it lasted for 3-6 months. Administration of doxorubicin 2 days before topotecan did not alter topotecan pharmacokinetics. Changes in topoisomerase mRNA levels were observed during chemotherapy.


CONCLUSIONS
The sequential combination of doxorubicin followed by topotecan is highly active in several chemotherapy refractory long, ovary, and esophageal cancers. Despite significant neutropenia, toxicity is manageable and well tolerated. Phase II trials to further evaluate the efficacy of this promising combination regimen against non-Hodgkin's lymphoma and lung cancer have been initiated.
Seiden
Michael V
MV
Department of Medicine, Massachusetts General Hospital, Boston 02114, USA. mseiden@partners.org
Ng
Shu-Wing
SW
Supko
Jeffrey G
JG
Ryan
David P
DP
Clark
Jeffrey W
JW
Lynch
Thomas
T
Huang
Kuan-Chun
KC
Kwiatkowski
David
D
Skarin
Arthur
A
Eder
Joseph P
JP
D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D017931:DNA Primers / Q000378:metabolism; D004264:DNA Topoisomerases, Type I / Q000235:genetics / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D012334:RNA, Neoplasm / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012449:Safety; D019772:Topotecan / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D016896:Treatment Outcome
D000951:Antigens, Neoplasm; D017931:DNA Primers; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D019772:Topotecan; D004317:Doxorubicin; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II