Eribulin is a synthetic analog of halichondrin B, and it inhibits microtubule function, leading to a block in the G2-M phase of the cell cycle. This agent appears to be less sensitive to the multidrug resistance-mediated P-glycoprotein efflux pump, and one of the advantages of this agent is that it has activity in drug-resistant tumors that overexpress P-glycoprotein. It is presently approved for the treatment of patients with metastatic breast cancer.
Etoposide is a semisynthetic derivative of podophyllotoxin, which is extracted from the mayapple root (Podophyllum peltatum). Intravenous and oral formulations of etoposide are approved for clinical use in the USA. Oral bioavailability is about 50%, requiring oral dosage to be twice that of intravenous dosage. Up to 30–50% of an administered dose of drug is excreted in the urine, and dose reduction is required in patients with renal dysfunction. Etoposide forms a complex with topoisomerase II, the enzyme responsible for cutting and religating double stranded DNA, and DNA, leading to inhibition of the functional activity of topoisomerase II with inhibition of DNA synthesis and function. Etoposide has clinical activity in germ cell cancer, small cell and NSCLC, Hodgkin’s and non-Hodgkin’s lymphomas, and gastric cancer. Major toxicities are listed in Table 54–4.
The camptothecins are natural products derived from the Camptotheca acuminata tree originally found in China; they inhibit the activity of topoisomerase I, the key enzyme responsible for cutting and religating single DNA strands. Inhibition of this enzyme results in DNA damage. Topotecan and irinotecan are the two camptothecin analogs used in clinical practice in the USA. Although they both inhibit the same molecular target, their spectrum of clinical activity is quite different.
Topotecan is indicated in the treatment of advanced ovarian cancer as second-line therapy following initial treatment with platinum-based chemotherapy. It is also approved as second-line therapy of small cell lung cancer. The main route of elimination is renal excretion, and dosage must be adjusted in patients with renal impairment. Irinotecan is a prodrug that is converted mainly in the liver by the carboxylesterase enzyme to the SN-38 metabolite, which is 1000-fold more potent as an inhibitor of topoisomerase I than the parent compound. In contrast to topotecan, irinotecan and SN-38 are mainly eliminated in bile and feces, and dose reduction is required in the setting of liver dysfunction. Irinotecan was originally approved as second-line monotherapy in patients with metastatic colorectal cancer who had failed fluorouracilbased therapy. It is now approved as first-line therapy when used in combination with 5-FU and leucovorin, and this combination is known as FOLFIRI. Myelosuppression and diarrhea are the two most common adverse events (Table 54–4). There are two forms of diarrhea: an early form that occurs within 24 hours after administration and is thought to be a cholinergic event effectively treated with atropine, and a late form that usually occurs 2–10 days after treatment. The late diarrhea can be severe, leading to significant electrolyte imbalance and dehydration in some cases.
Liposomal irinotecan is approved in combination with 5-FU and leucovorin for the treatment of metastatic adenocarcinoma of the pancreas after disease progression following gemcitabine-based therapy. The main adverse effects associated with the liposomal formulation are myelosuppression and GI toxicity with diarrhea and nausea and vomiting. Relatively little is known about the clinical pharmacology and metabolism of this liposomal formulation of irinotecan.