Capecitabine is a drug that requires the consecutive action of three enzymes: carboxylesterase 2 (CES 2), cytidine deaminase (CDD), and thymidine phosphorylase (TP) for transformation into 5-fluorouracil (5FU). The metabolism of 5FU requires the activity of thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) among other enzymes. The present study prospectively examined the possible relationship between the toxicity and efficacy of capecitabine and 14 different polymorphisms in CES 2, CDD, TS and DPD. Between 2003 and 2005, a total of 136 patients with advanced breast or colorectal cancer treated with capecitabine were prospectively enrolled. The presence of two polymorphisms (CDD 943insC and CES 2 Exon3 6046 G/A) were associated with a non-statistically significant higher incidence of grade 3 hand-foot syndrome (HFS) (p=0.07) and grade 3-4 diarrhoea (p=0.09), respectively. Patients heterozygous or homozygous for the polymorphism CES 2 5'UTR 823 C/G exhibited a significantly greater response rate to capecitabine, and time to progression of disease (59%, 8.7 months) than patients with the wild type gene sequence (32%, p=0.015; 5.3 months, p=0.014). For the first time, an association between a polymorphism in the CES2 gene and the efficacy of capecitabine has been described, providing preliminary evidence of its predictive and prognostic value.
Pancreatic cancer remains an aggressive disease with a 5 year survival rate of 5%. Only 15% of patients with pancreatic cancer are eligible for radical surgery. Evidence suggests a benefit on survival with adjuvant chemotherapy (gemcitabine o fluourouracil) after R1/R0 resection. Adjuvant chemoradiotherapy is also a valid option in patients with positive margins. Borderline resectable pancreatic cancer is defined as the involvement of the mesenteric vasculature with a limited extension. These tumors are technically resectable, but with a high risk of positive margins. Neoadjuvant treatment represents the best option for achieving an R0 resection. In advanced disease, two new chemotherapy treatment schemes (Folfirinox or Gemcitabine plus nab-paclitaxel) have showed improvements in overall survival compared with gemcitabine alone. Progress in pancreatic cancer treatment will require a better knowledge of the molecular biology of this disease, focusing on personalized cancer therapies in the near future.
We evaluated the antitumoral efficacy and safety of CPT-11 125 mg/m2 (weekly 90 min i.v. infusion; days 1, 8 and 15) combined with UFT (oral combination of tegafur and uracil) 200 mg/m2/day plus leucovorin (LV) 45 mg/m2/day (both divided into three separate oral doses every 8 h, days 1-21) every 4 weeks as first-line chemotherapy of metastatic colorectal cancer (CRC). Fifty-three patients > or =18 years old with histologically confirmed diagnosis of advanced CRC and bidimensionally measurable disease were enrolled. Three patients (6%) showed CR and 8 patients (15%) showed PR (ORR = 21% (95% CI, 10-32). Stable disease was reported in 19 patients (36%) [tumor control rate = 57% (95% CI, 43-70)]. The median time to progression and overall survival were 7.9 and 18.2 months, respectively (1-year rate = 74%; 2-years rate = 26%). CPT-11/UFT/LV treatment was well tolerated: the most reported grade 3/4 toxicities were neutropenia (11% of patients) and delayed diarrhea (28% of patients). No significant differences in response rate, survival or toxicity were found between younger (< or =65 years) and older patients (> 65 years). Weekly CPT-11 plus UFT/LV was found effective and safe as first-line chemotherapy for metastatic CRC. The addition of CPT-11 to UFT/LV doubled the response rate compared to the results previously reported with UFT/LV, while myelosuppression remained low.
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