Phase III comparison of two irinotecan dosing regimens in second-line therapy of metastatic colorectal cancer
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.
SourceAvailable from: PubMed Central[Show abstract] [Hide abstract]
ABSTRACT: To define the dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and pharmacokinetics (PK) of PEP02, a novel liposome-encapsulated irinotecan, in patients with advanced refractory solid tumors. Patients were enrolled in cohorts of one to three to receive escalating dose of PEP02 in a phase I trial. PEP02, from 60 to 180 mg/m(2), was given as a 90-min intravenous infusion, every 3 weeks. A total of 11 patients were enrolled into three dose levels: 60 (one patient), 120 (six patients) and 180 mg/m(2) (four patients). DLT was observed in three patients, one at 120 mg/m(2) (grade 3 catheter-related infection) and two at 180 mg/m(2) (grade 4 neutropenia lasting for >3 days in one, grade 4 hematological toxicities and grade 4 diarrhea in the other). MTD was determined as 120 mg/m(2). Comparing with those after free-form irinotecan in the literature, the dose-normalized PK of SN-38 (the active metabolite) after PEP02 was characterized by lower C max, prolonged terminal half-life and higher AUC but with significant inter-individual variation. One patient who died of treatment-related toxicity had significantly higher C max and AUC levels of SN-38 than those of the other three patients at 180 mg/m(2). Post hoc pharmacogenetic study showed that the patient had a combined heterozygosity genotype of UGT1A1*6/*28. Two patients had objective tumor response. PEP02 apparently modified the PK parameters of irinotecan and SN-38 by liposome encapsulation. The MTD of PEP02 monotherapy at 3-week interval is 120 mg/m(2), which will be the recommended dose for future studies.Cancer Chemotherapy and Pharmacology 01/2015; 75(3). DOI:10.1007/s00280-014-2671-x · 2.57 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: The aim of this study was to compare the efficacy, safety and survival rate of a treatment regimen comprising capecitabine plus irinotecan (XELIRI) to those of a standard regimen comprising leucovorin, fluorouracil and irinotecan (FOLFIRI), to determine the correlation among the inherited genetic variations in UGT1A1, UGT1A7 and UGT1A9. A total of 84 consecutive patients with histologically confirmed metastatic colorectal cancer (mCRC) were included in the study. All patients were treated with FOLFIRI or XELIRI. The median progression-free survival time was 4.4 months for FOLFIRI and 5.7 months for XELIRI (hazard ratio=1.35; 95% confidence interval, 0.83-2.21; P=0.22). When compared with FOLFIRI (6.34%), XELIRI was associated with lower rates of severe toxicity (3.29) (P=0.026) and similar disease control rates (69.57% for FOLFIRI and 61.11% for XELIRI; P=0.49). In total, 17 single nucleotide polymorphisms were identified, five of which revealed an association with grade 3/4 neutropenia, including UGT1A7*4; however, UGT1A1*28 and UGT1A1*6, which have been previously reported, were not significant. Additionally, H2 haplotypes, which include UGT1A9*22, and H5 and H7 haplotypes, which include UGT1A7*2, UGT1A7*3 and UGT1A7*4, were associated with a higher risk of severe neutropenia. In conclusion, XELIRI is an effective treatment regimen with acceptable response rates and tolerability for mCRC patients as a second-line treatment. Furthermore, inherited genetic variations in UGT1A1, UGT1A7 and UGT1A9 are associated with grade 3/4 neutropenia.Oncology letters 10/2014; 8(4):1864-1872. DOI:10.3892/ol.2014.2335 · 0.99 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: Inflammation is an important component of cancer diathesis and treatment-refractory inflammation is a feature of many chronic degenerative lung diseases. HSP90 is a 90kDa protein which functions as an ATP-dependent molecular chaperone that regulates the signalling conformation and expression of multiple protein client proteins especially oncogenic mediators. HSP90 inhibitors are in clinical development as cancer therapies but the myeleosuppressive and neutropenic effect of first generation geldanamycin-class inhibitors has confounded studies on the effects on HSP90 inhibitors on inflammation. To address this we assessed the ability of Ganetespib, a non-geldanamycin HSP90 blocker, to suppress lipopolysaccharide (LPS)-induced cellular infiltrates, proteases and inflammatory mediator and transcriptional profiles. Ganetespib (10-100mg/kg, i.v.) did not directly cause myelosuppression, as assessed by video micrography and basal blood cell count, but it strongly and dose-dependently suppressed LPS-induced neutrophil mobilization into blood and neutrophil- and mononuclear cell-rich steroid-refractory lung inflammation. Ganetespib also suppressed B cell and NK cell accumulation, inflammatory cytokine and chemokine induction and MMP9 levels. These data identify non-myelosuppresssive HSP90 inhibitors as potential therapies for inflammatory diseases refractory to conventional therapy, in particular those of the lung.PLoS ONE 01/2015; 10(1):e0114975. DOI:10.1371/journal.pone.0114975 · 3.53 Impact Factor