13557 Chronotherapy studies in pretreated CRC cancer pts showed that 6 hrs chronomodulated CPT11 infusion from 2 to 8 a.m., alone or combined with 5FU+AF±OHP, is less toxic than the standard 90 min. infusion, and CPT11-SN38 convertion efficency is improved with an higer objective response rate. Objective of this study was evaluation of CPT11 pharmacokinetics after hepatic i.a. perfusion according to infusion time and circadian patient pattern. To evaluate patient circadian pattern, serum levels of prolactin and cortisol were detected at 2–6, 4 pm and 2–6, 4 -8 pm respectively. CPT11 and SN38 serum levels were detected, according to two different time schedules, following the HPLC method. Every pt received 240 mg/mq i.a. CPT11 perfusion alternating daily with nightly schedule: from NOV04 to FEB05 5 metastatic CRC patients were treated. All pts concluded all programmed cycles. No cycle was delayed due to toxicity. Haematological, hepatic and g.i. G 3–4 (NCI) toxicity were not observed (only neutropenia G1 in the female subject). Circadian organization seems to be progressively lost according to cycle number. At 3rd cycle, cyrcadian levels of cortisol and prolactin are lost in all pts. Kinetic data suggests for a progressive reduction of liver enzymatic capability; this is probably due to cumulative liver drug toxicity: this phenomenon is clearly evidenced in female subject but is also signicative in the male subjects (see Table). These preliminary data show enormous PK/PD interpatient variability and a significative AUC reduction 2nd cycle vs 1st and 3rd vs 2nd; due to this unespected observation we are not able to evaluate cyrcadian oscillation of enzymatic systems: in order to fully understand these data we decided to perform polimorphism assesment for UGT1A1,Carboxil Esterase isoform2 and ABC transporters genes.This analysis will be performed on paraffin included samples for the first 5 pts and on fresh tissue for the next pt set. [Table: see text] No significant financial relationships to disclose.
416 Background: Advances in understanding the mechanisms underlying diseases and drug responses are creating increasing opportunities to offer safer and more effective treatments to individual patients (pts). Biomarkers are needed for predicting likelihood of therapeutic safety and efficacy in each individual pt. Down-regulation of core clock gene PER2 in tumors predicted for poor survival in pts with metastatic colorectal cancer (Jacobelli. J Clin Oncol. 26: 2008 May 20 suppl; abstr 11032). Methods: A clinical data base and tissue bank involving primary tumor (T) and healthy adjacent colon mucosa (C) from 139 pts treated with circadian-shaped or standard infusion of (A)-single-agent irinotecan (63 pts) or (B) in combination with oxaliplatin and 5FU (76 pts) for previously-treated metastatic colorectal cancer was established and tissues were collected. Clinical relevance of constitutive or acquired single nucleotide polymorphisms (SNPs) for 5 metabolism (ABCB1, ABCB2, CES2, TOP1, UGT1A1) and for two PER2 SNP's (A4572G and C3968T). Results: No acquired mutation in the genes analysed was found (100% T and C concordance). The incidence of grade 3-4 toxic event of any kind was significantly lower in women as compared to men in A population(39% vs 76%, p=0.007) and in A+B population (p=0.05), independently from other factors (p=0.02) this difference is lost if you consider only B population where oxaliplatin is added (p=0.5). No SNP in metabolism genes predicted for toxicity in this cohort. Conversely, SNPs in core clock gene PER2 (1 pt with A4572G and 4 pts C3968T) were significantly associated with higher incidence of G3-4 toxicity (100% in polymorphic pts. vs 17.2% in wild type pts, p=0.01). Conclusions: Irinotecan tolerability is sex dependent and woman has significative low incidence of toxic effects. We demonstrated for the first time an association between constitutive SNPs in a core clock gene and toxicity, further supporting the relevance of the circadian timing system in chemotherapy tolerability. Moreover, our findings are in good agreement with data in mice, supporting the hypothesis that sex determines two chronotoxicity classes in patients with metastatic colorectal cancer. No significant financial relationships to disclose.
14572 Background: FOLFOX4 schedule represents the standard treatment for metastatic colorectal cancer in EU, but is characterized by relevant adverse effects like G3–4 neutropenia in 42 % of patients (data from MOSAIC study). Adjustment of chemotherapy delivery schedule to the circadian timing system allows a significative improvement of tolerability. Objective of this multicentric observational study is the evaluation of therapeutic index of a OHP and 5-FU + AF based schedule at the same doses of FOLFOX 4, but administered according to a chronomodulated schedule (FLOX-1). Methods: From November 2005 to December 2006, we treated 41 metastatic colorectal cancer patients (19 male and 22 female, average age 65) with OHP 85 mg/m2/d1q14 sinusoidal 12 hour infusion with flow rate peak at 04.00 PM; 5-FU 1000 mg and AF 100 mg/m2/d1–2q14 sinusoidal 12 hour infusion with flow rate peak at 04.00 AM: a total of 258 cycles (5.5 average for patient) were administered using Melodie infusional programmable system (138 cycles) and CIP preprogrammed disposable system (128 cycles), all in homecare regimen. These data confirm a significative tolerability improvement of OHP, 5-FU and AF schedule when infused according to a chronomulated infusion prophile in metastatic colorectal cancer patients. Results: Overall average dose intensity was 39.1 mg/m2/w for OHP and 907.5 mg/m2/w for 5-FU respectively. No G3-G4 haematological, hepatic and neurological toxicity were observed. ORR (CR+PR) was 41%. No patient has been treated with G-CSF. Conclusions: These data confirm a significative tolerability improvement of OHP, 5-FU and AF schedule when infused according to a chronomulated infusion prophile in metastatic colorectal cancer patients. No significant financial relationships to disclose.
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