Statin use is not associated with improved progression free survival in cetuximab treated KRAS mutant metastatic colorectal cancer patients: results from the CAIRO2 study.

Statins may inhibit the expression of the mutant KRAS phenotype by preventing the prenylation and thus the activation of the KRAS protein. This study was aimed at retrospectively evaluating the effect of statin use on outcome in KRAS mutant metastatic colorectal cancer patients (mCRC) treated with cetuximab. Treatment data were obtained from patients who were treated with capecitabine, oxaliplatin bevacizumab ± cetuximab in the phase III CAIRO2 study. A total of 529 patients were included in this study, of whom 78 patients were on statin therapy. In patients with a KRAS wild type tumor (n = 321) the median PFS was 10.3 vs. 11.4 months for non-users compared to statin users and in patients with a KRAS mutant tumor (n = 208) this was 7.6 vs. 6.2 months, respectively. The hazard ratio (HR) for PFS for statin users was 1.12 (95% confidence interval 0.78-1.61) and was not influenced by treatment arm, KRAS mutation status or the KRAS*statin interaction. Statin use adjusted for covariates was not associated with increased PFS (HR = 1.01, 95% confidence interval 0.71-1.54). In patients with a KRAS wild type tumor the median OS for non-users compared to statin users was 22.4 vs. 19.8 months and in the KRAS mutant tumor group the OS was 18.1 vs. 14.5 months. OS was significantly shorter in statin users versus non-users (HR = 1.54; 95% confidence interval 1.06-2.22). However, statin use, adjusted for covariates was not associated with increased OS (HR = 1.41, 95% confidence interval 0.95-2.10). In conclusion, the use of statins at time of diagnosis was not associated with an improved PFS in KRAS mutant mCRC patients treated with chemotherapy and bevacizumab plus cetuximab.

Exposure to phototoxic NSAIDs and quinolones is associated with an increased risk of melanoma.

PURPOSE: Ultraviolet radiation exposure is the most important exogenous risk factor for cutaneous malignancies. It is possible that phototoxic drugs promote the development of cutaneous melanoma (CM) by intensifying the effect of ultraviolet light on the skin. We investigated the association between the use of common systemic phototoxic drugs and development of CM. METHODS: This study was a case-control study in a Dutch population-based cohort. The drug dispensing data was obtained from PHARMO, a Dutch drug dispensing and hospital admissions registry, and linked to PALGA, the nationwide pathology network of the Netherlands. The cases were patients diagnosed with pathologically confirmed primary CM between 1991 and 2004. Controls were sampled from the PHARMO population. Exposure to systemic phototoxic drugs was measured and included antimicrobial agents, diuretics, antipsychotic drugs, antidiabetic drugs, cardiac drugs, antimalarials and nonsteroidal anti-inflammatory drugs (NSAIDs). A multivariate conditional logistic regression analysis was performed to study the association between exposure to phototoxic drugs and CM. RESULTS: The study population included 1,318 cases and 6,786 controls. Any phototoxic drug during the study period was dispensed for 46 % of the cases and 43 % of the controls (p = 0.012). The use of quinolones [odds ratio (OR) 1.33, 95 % confidence interval (CI) 1.01-1.76] and propionic acid derivative NSAIDs (OR 1.33, 95 % CI 1.14-1.54) had a positive association with CM. CONCLUSIONS: Our study shows that the use of phototoxic drugs is associated with an increased risk of developing CM. Even a short-term use of phototoxic quinolones and propionic acid derivative NSAIDs may increase the risk for CM. Patient education to promote sun-protective behaviour is essential to avoid immediate adverse effects and possible long-term effects of phototoxic drugs.

Chemoprevention for keratinocytic (pre)cancers: balancing the risks and benefits.

QUESTION: Can celecoxib reduce the incidence of actinic keratoses (AKs) and keratinocytic cancers? DESIGN: Randomized, double-blind, placebo-controlled phase 2-3 clinical trial. SETTING: Eight centers in the United States participated and included 240 patients from January 2001 to November 2006, when the Food and Drug Administration requested termination of this trial after the worldwide withdrawal of rofecoxib. PATIENTS: The study population comprised individuals 18 years or older with Fitzpatrick skin type I to III, with 10 to 40 AKs on the upper extremities, neck, face, and scalp at baseline and a previous histological diagnosis of a keratinocytic (pre)malignant neoplasm. INTERVENTION: Celecoxib (200 mg) or placebo twice daily. MAIN OUTCOME MEASURE: The ratio of new AKs per patient at completion of the study to the number of AKs at randomization. EXPLORATORY POST HOC ANALYSIS: The mean cumulative number of keratinocytic skin cancers per patient. RESULTS: There was no difference in the incidence of AKs between the 2 groups at month 9 after randomization. The adjusted rate ratios for the celecoxib arm compared with the placebo arm were 0.41 (95% CI, 0.23-0.72) for keratinocytic skin cancers, 0.40 (95% CI, 0.18-0.93) for basal cell carcinomas (BCCs), and 0.42 (95% CI, 0.19-0.93) for squamous cell carcinomas (SCCs). CONCLUSION: Celecoxib might be effective for prevention of keratinocytic cancers but not for actinic keratoses.

Epidemiology of extracutaneous melanoma in the Netherlands.

BACKGROUND: Reliable population-based incidence and survival data on extracutaneous melanoma (ECM) are sparse. METHODS: Incidence data (1989-2006) from the Netherlands Cancer Registry were combined with vital status on January 1, 2008. Age-adjusted annual incidence rates were calculated by direct standardization, and the estimated annual percentage change was estimated to detect changing trends in incidence. Additionally, we carried out cohort-based relative survival analysis. RESULTS: Ocular melanomas were the most common ECM subsite with European standardized incidence rates (ESR) of 10.7 and 8.2 per 1,000,000 person-years for males and females, respectively. In comparison, for cutaneous melanoma (CM), the ESRs for men and women were 122 and 155 per million person-years, respectively. No statistically significant trends in the incidence of ECM were detected, whereas an annual increase of 4.4% for men and 3.6% for women was detected in the incidence of CM. Relative survival for ECM was poor, but differed largely between anatomic subtypes ranging from a 5-year relative survival of 74% for ocular melanomas to 15% for certain subsites of mucosal melanomas. CONCLUSIONS: Of all ECM subsites, ocular melanomas had the highest incidence and the best survival. Mucosal melanomas were the second most frequent subsite of ECM. Five-year relative survival for all ECM subtypes was worse if compared with CM. No statistically significant trends in the incidence of (subsites of) ECM were determined. IMPACT: This study gives insight into the relative sizes of the different subgroups of ECM as well as an estimate of 5-year survival, which varies substantially by subsite.