Irinotecan in Patients with Hepatic or Renal Dysfunction or with Prior Pelvic Radiation

Abstract & Commentary

Synopsis: Patients with elevated bilirubin treated with irinotecan have an increased risk of toxicity, and a dose reduction is recommended. Patients with elevated AST, creatinine or prior pelvic radiation do not appear to have increased sensitivity to irinotecan, but the data are not adequate to support a specific dosing recommendation.

Source: Venook, et al. Ann Oncol. 2003;14:1783-1790.

Irinotecan (cpt-11; 7-ethyl-10-[4(-1-piperidino)-1-piperidino] carbonyloxy camptothecin) is a semisynthetic derivative of the natural alkaloid camptothecin. It is a prodrug that belongs to the class of antineoplastic agents called topoisomerase I inhibitors. In vivo, irinotecan is converted by carboxylesterases to its most active cytotoxic metabolite, 7-ethyl-10-hydroxy-camptothecin (SN-38), which exerts its cytotoxicity by generating intermediate forms of drug-stabilized covalent DNA, topoisomerase-I complexes. It has been used primarily in the treatment of metastatic colorectal cancer but also has activity in non-small-cell lung cancer. It can be administered singly in either a weekly or 3-week schedule and is often combined with leucovorin and 5-fluorouracil. The dose-limiting toxicities of irinotecan are diarrhea and myelosuppression. Diarrhea appears to be due to intraluminal exposure to SN-38, although it is controversial as to the importance of biliary excretion of SN-38 vs intraluminal formation by beta glucuronidases. Aggressive early intervention with loperamide can reduce the severity of the toxicity. There has been concern over the toxicity of this agent, particularly when combined with fluoropyrimdines and in patients with hepatic and renal dysfunction. This was in part due to the biliary index, which has been demonstrated to correlate with the severity of diarrhea on the weekly schedule.1 There also has been concern for the dosing of irinotecan in hepatic dysfunction, since many patients with metastatic colorectal cancer may have extensive liver metastases. The Cancer and Leukemia Group B has conducted trials with paclitaxel and gemcitabine in patients with end organ dysfunction.2,3 Therefore, the current trial was initiated.

Comment by Stuart M. Lichtman, MD, FACP

A Phase I type study design was used. Adult patients with biopsy proven solid tumors or lymphomas that were refractory to standard therapy or for which no standard therapy existed were eligible for the study. Patients were assigned to 1 of 4 treatment cohorts: I, aspartate aminotransferase (AST) ³ 3 ´ upper limit of normal and direct bilirubin < 1.0 mg/dL; II, direct bilirubin 1.0-7.0 mg/dL; III, creatinine 1.6-5.0 mg/dL with normal liver function; or IV, prior pelvic XRT with normal liver and renal function. The starting dose for patients in cohorts I, III, and IV was 225 mg/m2 and cohort II 145 mg/m2 by 90-min infusion every 3 weeks. One cycle consisted of 2 treatments. Three patients were accrued to each dose level. If none of these 3 patients experienced dose-limiting toxicity, the dose was to be increased in subsequent groups to a maximum of 350 mg/m2. Pharmacokinetic analyses were performed.

Thirty-five patients were enrolled in the study. Twenty-nine patients had received prior chemotherapy. Metastatic gastrointestinal cancer was the underlying disease in 13 patients, 8 of the patients had primary liver cancer and 9 patients had genitourinary cancers. The CALGB performance status was 0-1 in all but 5 patients. Seven patients encountered a dose limiting toxicity during the first cycle; 5 of the 7 had prior chemotherapy, and 2 had prior radiotherapy. The most common dose limiting toxicity (DLT) was neutropenia, seen in 4 patients, which manifested as nadir counts rather than protracted neutropenia. In cohort II, 2 of the DLTs were neutropenia in patients with baseline direct bilirubins of 4.5 and 1.5 mg/dL, respectively, and the other DLT was worsening liver function in a patient with a baseline direct bilirubin of 1.4 mg/dL. The 2 patients with DLT in the renal dysfunction cohort had grade 4 diarrhea and neutropenia with calculated creatinine clearances of 36 and 32 mL/min, respectively. No patient who had a DLT was re-dosed with irinotecan.

There were no significant differences in the pharmacokinetic parameter estimates for irinotecan or its metabolites between patients with renal impairment and those with prior radiotherapy. In comparison, patients in cohort II had significant, clinically relevant decreases in irinotecan clearance. Irinotecan clearance was estimated to be reduced by 35% in cohort II compared with cohorts III and IV. A large variability within the cohort groups prevented detection of significant differences in the fraction of the parent compound metabolized among cohorts. Systemic exposure was similar across the cohorts.

This study was designed to make the dosing of chemotherapy in the patients with organ dysfunction a more precise exercise. It has long been one of empiricism. With the heterogeneity of the population studied precise dosing recommendations could not made. It was determined that patients with elevated direct bilirubin should be treated with irinotecan at reduced doses. The dosing in patients with renal dysfunction could not be determined as no patients with creatinines above 3.5 mg/dL were evaluated and the doses used were less than the standard every 3-week dosing.4 This study was based on a 3-week dosing schedule and it is uncertain whether it can be extrapolated to combination therapies are those used weekly. However, the results of the study are a reminder that the data generated in early Phase I or II trials are not generalizable to patients with organ dysfunction.

Dr. Lichtman is Associate Professor of Medicine NYU School of Medicine Division of Oncology; Don Monti Division of Medical Oncology North Shore University Hospital, Manhasset, NY.

References

1. Mick R, et al. J Clin Oncol. 1996;14:2012-2019.

2. Venook AP, et al. J Clin Oncol. 1998;16: 1811-1819.

3. Venook AP, et al. J Clin Oncol. 2000:18: 2780-2787.

4. Fuchs CS, et al. J Clin Oncol. 2003;21:807-814.