Abstract
4043 Background: The purpose of this study was to determine the maximum tolerated dose (MTD) of CDDP/TXT/CPT-11 in p with advanced esophagogastric cancer. XPD and UGT1A1 polymorphisms were also analyzed to examine their relationship with the tolerance and activity of this triplet. The XPD heterozygotes Lys751Gln and Asp312Asn have been linked to lower DNA repair capacity and better outcome with cisplatin-based regimens. UGT1A1*28 polymorphisms can determine toxicity and activity of CPT-11 by decreasing SN-38 inactivation Methods: We assessed XPD and UGT1A1 polymorphisms in blood samples of chemotherapy-naïve p with advanced esophageal and gastric cancer treated in a phase I dose-escalation study with CDDP (60 mg/m2 d1), TXT (25–30 mg/m2 d 1&8), CPT-11 (50–70 mg/m2 d1&8) every 3 weeks Results: 27 p were included: median age 59 years; 24 males; 74% Karnofsky index > 80%; esophagus: 8 p, G-E junction: 5 p, gastric: 14 p; 16 p (60%) had liver metastases. MTD was reached at level III (CDDP:60 d1, TXT 30 d1&8, CPT-11 60 d1&8). 3 of 4 p had febrile neutropenia, asthenia G3 and diarrhea G4. Recommended dose (RD) was established at level II (CDDP:60 d1, TXT 25 d1&8, CPT-11:60 d1&8). An additional cohort of 9 p was treated at the RD level. Objective response was observed in 14 of 25 patients (56%) with measurable disease (4 CR, 10 PR). Median survival is 14 months (95%C.I, 5.4–22.5). Frequencies of XPD polymorphisms: 9 Lys751Lys, 16 Lys751Gln, 2 Gln751Gln, 10 Asp312Asp, 14 Asp312Asn, 3 Asn312Asn. No differences in survival were observed according to XPD polymorphisms. Median survival was not reached in 15 p heterozygous for UGT1A1*28 genotype, compared to 9 months in 12 p with wild-type UGT1A1 (P=0.07). 8 of 15 p (53%) with UGT1A1*28 genotype had grade 3–4 toxicity, compared to 4 of 12 p (33%) with wild-type UGT1A1 (P=0.25). Conclusions: CDDP/TXT/CPT-11 is a feasible regimen with a promising activity. Patients with UGT1A1*28 genotype showed a tendency towards higher toxicity but with improved survival benefit. No significant financial relationships to disclose.
Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
