Time trends in colorectal cancer early postoperative mortality. A French 25-year population-based study.

BACKGROUND: Postoperative mortality after resection of colorectal cancer is an important issue. The aim of this study was to assess early postoperative mortality in a well-defined French population. METHODS: Data on 30- and 90-day postoperative mortality after resection for colorectal cancer were extracted from the digestive cancer registry of Burgundy. Time trends of postoperative mortality between 1989 and 2013 were described for the large population. Case-control studies (death within 30 or 90 days = cases, alive at 90 days = controls) focused on the association between postoperative mortality and surgical approach, obesity and other comorbidities over the last [2010-2013] period, using conditional logistic regressions. RESULTS: Among the 11,448 concerned patients, 30- and 90-day postoperative mortalities were 4.9 and 7.2%. Thirty-day operative mortality decreased from 7.2% (1989-1993) to 4.4% (2010-2013; p < 0.001) for colon cancer and from 4.2 to 3.3% for rectal cancer (NS). Diagnosis before 1997, male gender, advanced age, emergency surgery and palliative resection were associated with a significantly higher 30- and 90-day mortality rate. The univariate risk of mortality was two to three times higher for conventional open laparotomy and conversion than for laparoscopy-assisted surgery. The surgical approach was no longer significant in multivariate analysis. Emergency surgery and comorbidities were associated with higher 30- and 90-day postoperative mortality, whereas obesity was not specific. CONCLUSION: Postoperative mortality after colorectal resection decreased over time. Surgical approach had no influence on early mortality. Improvement in the management of the elderly and patients with comorbidities is a challenge to reduce postoperative mortality in the future.

Pharmacokinetic drug-drug interactions of tyrosine kinase inhibitors: A focus on cytochrome P450, transporters, and acid suppression therapy.

The extensive use of tyrosine kinase inhibitors (TKI's) in hematology and oncology has shown that these drugs have a significant potential for drug-drug interactions. Since these drugs have a rather low therapeutic window, some drug interactions are of particular clinical relevance either on drug toxicity or on patient's response. Significant interactions occur with concomitant use of acid-suppressive therapy leading to a decreased oral bioavailability. However, such interactions are drug dependent according to their solubility pattern and to the duration of action of acid-suppressive therapy, which is coprescribed. Significant interactions occur by inhibition or induction of CYP450 3A4 which is the main metabolic pathway of TKIs. However, minor metabolic pathways should also be paid attention to. Interactions involving efflux and influx transporters should also be considered occurring for some TKIs. Genetic polymorphism in drug metabolism as well as in drug transport is a factor of variability in drug exposure, which could modulate the magnitude of drug-drug interactions (DDIs). It should be noticed that TKIs can also be at the origin of drug interactions by altering the pharmacokinetics of coprescribed drugs. Since cancer patients are given many drugs either for supportive care or for the treatment of drug toxicity, and to the fact that the oldest patients are polymedicated, a clear understanding of DDIs with TKIs is of interest. The objectives of this review are to provide an overview of the mechanisms of DDIs with TKIs and to provide to physicians and pharmacists recommendations to manage these DDIs in their clinical practice.