Camptothecin is an alkaloid obtained from the Camptotheca acuminata tree. The original clinical preparation, camptothecin sodium, was evaluated in clinical trials in the late 1960s and early 1970s, but was abandoned due to severe and unpredictable hemorrhagic cystitis.[1-3] A semisynthetic derivative of camptothecin is irinotecan(Drug information on irinotecan) (CPT-11, Camptosar), with higher water solubility, greater in vitro and in vivo activity, and milder and more predictable toxicity than camptothecin.[4-6]
Camptothecin and its derivative, irinotecan, are potent inhibitors of topoisomerase I, an enzyme normally active during DNA replication. Topoisomerase I induces transient breaks in a single strand of DNA, which release the torsional strain caused by synthesis of a new strand of DNA or RNA around a double helix. The campthothecins target this topoisomerase I-DNA complex, stabilize it, and inhibit the reannealing of the parent DNA. When an advancing replication fork collides with the camptothecin-topoisomerase I-DNA complex, double-stranded DNA breaks occur that lead to cell death.[7,8]
Irinotecan has been evaluated using several schedules and dosages, the most frequent being weekly for 4 weeks with 1- or 2-week treatment breaks. Alternatively, in Europe, where the drug has also been developed primarily for the treatment of colorectal cancer, single doses of 350 mg/m² have been given every 3 weeks with response rates ranging from 14% to 18%, depending on the extent of previous therapy.[9,10] The every-21-days irinotecan schedule is more attractive for the treatment of lymphoma because it will be easier to combine with other myelosuppressive drugs that are active in lymphoma, which are also usually given every 21 days, and can be supported by hematopoietic growth factors to minimize or prevent neutropenia.
Based on these considerations, we decided to investigate the clinical activity of irinotecan administered at 300 mg/m² every 21 days[11] in patients with relapsed or refractory non-Hodgkin’s lymphoma (NHL).
Patients and Methods
Patients were eligible for study entry if they had histologically confirmed relapsed or refractory NHL. Relapsed disease indicates recurrence after a complete or partial response to the initial regimen. Refractory disease indicates less than a partial response or progression during the initial regimen. Eligible patients had bidimensionally measurable disease, a Zubrod performance status ≤ 2, normal serum creatinine and bilirubin levels, serum transaminase levels £ 4 times the upper normal limit, absolute granulocyte count ³ 1,500/µL, and platelet count ³ 100,000/µL. Patients with central nervous system involvement or human immunodeficiency virus infection, or who had been treated with three or more previous regimens or with transplantation of stem cells or bone marrow, were ineligible. The study was approved by the Investigational Review Board and the National Cancer Institute for activation to the Cancer Community Oncology Program. All patients signed informed consent.
