Article

Fuchs CS, Moore MR, Harker G, Villa L, Rinaldi D, Hecht JRPhase III comparison of two irinotecan dosing regimens in second-line therapy of metastatic colorectal cancer. J Clin Oncol 21: 807-814

Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Journal of Clinical Oncology (Impact Factor: 18.43). 03/2003; 21(5):807-14. DOI: 10.1200/JCO.2003.08.058
Source: PubMed

ABSTRACT

Randomized trials in fluorouracil (FU)-refractory colorectal cancer demonstrate significant survival advantages for patients receiving irinotecan. We prospectively compared the efficacy and tolerability of two irinotecan regimens (once a week for 4 weeks followed by a 2-week rest period [weekly] v once every 3 weeks) in such patients.
This multicenter, open-label, phase III study randomly assigned patients in a 1:2 ratio to irinotecan given either weekly (125 mg/m(2)) or once every 3 weeks (350 mg/m(2), or 300 mg/m(2) in patients who were >/= 70 years of age, who had Eastern Cooperative Oncology Group performance status equal to 2, or who had prior pelvic irradiation).
With median follow-up of 15.8 months, there was no significant difference in 1-year survival (46% v 41%, respectively; P =.42), median survival (9.9 v 9.9 months, respectively; P =.43), or median time to progression (4.0 v 3.0 months, respectively; P =.54) between the two regimens. Grade 3/4 diarrhea occurred in 36% of patients treated weekly and in 19% of those treated once every 3 weeks (P =.002). Grade 3/4 neutropenia occurred in 29% of patients treated weekly and 34% of those treated once every 3 weeks (P =.35). Treatment-related mortality occurred in five patients (5.3%) receiving irinotecan weekly and three patients (1.6%) given therapy once every 3 weeks (P =.12). Global quality of life was not statistically different between treatment groups.
Irinotecan schedules of weekly and of once every 3 weeks demonstrated similar efficacy and quality of life in patients with FU-refractory, metastatic colorectal cancer. The regimen of once every 3 weeks was associated with a significantly lower incidence of severe diarrhea.

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    • "Second line irinotecan (CPT-11), in 5-fluorouracil (5-FU) refractory MCRC pts, achieved median PFS of 3–4 months and OS 9.9 months (12,13). Doublet FOLFOX6 or FOLFIRI showed similar efficacy (7), with <2% metastasectomies. "
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    ABSTRACT: Clinical outcome post-progression to first-line triplet chemotherapy (CT) plus bevacizumab (FIr-B/FOx) was evaluated in metastatic colorectal cancer (MCRC) patients (pts). Second-line treatment was selected according to fitness, KRAS genotype, previous efficacy and safety. Efficacy was evaluated and compared according to treatment or KRAS genotype, using log-rank analysis. Among 54 pts, median overall survival (OS) post-progression was 12 months, significantly better in 40 (74.1%) treated compared to 14 (25.9%) who died without further treatment. Second-line surgical treatment, 4 pts (7.4%), medical treatment, 36 pts (66.7%): triplet CT plus targeted agent, 10 (18.5%); triplet regimens, 19 (35.2%); doublet/monotherapy, 7 (13%). At follow-up of 14 months, objective response rate (ORR) was 38%, metastasectomies 12.5%, progression-free survival (PFS) 10 months, OS 14 months. According to treatment, ORR, metastasectomies, PFS and OS were significantly favourable in triplet CT plus targeted agent compared to triplet, respectively: 80%, 40%, 13 months, not reached; 28%, 6%, 8 months, 11 months. PFS and OS were significantly worse in c.35 G>A mutant compared to wild-type and/or other mutant patients. Prognosis after progression to first‑line FIr-B/FOx may be significantly favourable in MCRC pts re-challenged with intensive regimens, and unfavourable in c.35 G>A KRAS mutant patients.
    Full-text · Article · Nov 2013 · International Journal of Oncology
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    • "CPT-11 {irinotecan; 7-ethyl-10-[4-(1-piperidino)-1-piperidino]} is employed worldwide for the treatment of a variety of solid malignancies, but its efficacy is often limited by severe gastrointestinal (GI) toxicity (Rothenberg et al., 1996; Rougier et al., 1997, 1998; Cunningham et al., 1998; Saltz et al., 2000; Fuchs et al., 2003; Hu et al., 2006; Kurita et al., 2011). CPT-11 is most frequently used in first-and second-line treatment of metastatic colon cancers, typically in combination with other agents (Smith et al., 2006; Kambe et al., 2012). "
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    ABSTRACT: Bacterial β-glucuronidases expressed by the symbiotic intestinal microbiota appear to play important roles in drug-induced epithelial cell toxicity in the gastrointestinal (GI) tract. For the anticancer drug CPT-11 (Irinotecan) and the non-steroidal anti-inflammatory drug diclofenac, it has been shown that removal of the glucuronide moieties from drug metabolites by bacterial β-glucuronidases in the GI lumen can significantly damage the intestinal epithelium. Furthermore, selective disruption of bacterial β-glucuronidases by small molecule inhibitors alleviates these side effects, which, for CPT-11, can be dose-limiting. Here we characterize novel microbial β-glucuronidase inhibitors that inhibit E. coli β-glucuronidase in vitro with Ki values between 180 nM and 2 µM, and disrupt the enzyme in E. coli cells with EC50 values as low as 300 nM. All compounds are selective for E. coli β-glucuronidase without inhibiting purified mammalian β-glucuronidase, and they do not impact the survival of either bacterial or mammalian cells. The 2.8 Å resolution crystal structure of one inhibitor bound to E. coli β-glucuronidase demonstrates that it contacts and orders only a portion of the "bacterial loop" present in microbial, but not mammalian, β-glucuronidases. The most potent compound examined in this group was found to protect mice against CPT-11-induced diarrhea. Taken together, these data advance our understanding of the chemical and structural basis of selective microbial β-glucuronidase inhibition, which may improve human drug efficacy and toxicity.
    Preview · Article · May 2013 · Molecular pharmacology
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    • "The most common grade 3 or 4 adverse events observed in a phase III trial of single-agent irinotecan administered every 3 weeks were neutropenia, diarrhoea, and vomiting (Fuchs et al, 2003). "
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    ABSTRACT: Sunitinib is a multitargeted, oral tyrosine kinase inhibitor with antitumour and antiangiogenic activity. We investigated the safety and pharmacokinetics of sunitinib in combination with irinotecan in patients with advanced, refractory solid tumours. Sunitinib was initially administered once daily at 37.5 mg per day on days 1-14 of a 21-day cycle, in which irinotecan 250 mg m(-2) was given on day 1. In a second cohort, the sunitinib dose was reduced to 25 mg per day. Blood samples were collected for pharmacokinetic studies. In the sunitinib 37.5 mg per day cohort, 3 out of 10 evaluable patients had objective responses, but dose-limiting toxicities (DLTs) of neutropenia, pneumococcal sepsis, and fatigue were observed. There were no DLTs in the sunitinib 25 mg per day cohort. Paired observations of pharmacokinetic parameter values of sunitinib and irinotecan alone vs the combination did not reveal significant drug-drug interactions. The maximum tolerated dose was defined as sunitinib 25 mg per day (days 1-14) with irinotecan 250 mg m(-2) (day 1), but no activity was observed at this dose. Although a higher sunitinib dose of 37.5 mg per day (days 1-14) with irinotecan showed preliminary evidence of antitumour activity, this dose was poorly tolerated. Therefore, this particular combination will not be pursued for further studies.
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