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Background: NF-kappaB is one of the nuclear effectors of EGFR activation. There are reports showing that NF-kappaB expression and activity is enhanced after nicotine treatment. Some data demonstrated that NF-kappaB activation plays a role in the induction of resistance to cetuximab and irinotecan in advanced colorectal tumors. The aim of this study was to evaluate the effect of cigarette smoking on cetuximab efficacy in advanced colorectal cancer patients., Methods: We retrospectively analysed the smoking habits of 200 patients treated with a variety of anticancer regimens containing cetuximab for advanced colorectal cancer. All patients were irinotecan-resistant and received an oxaliplatin-based first line treatment. We divided our patient population as follows: no previous smoking habit, previous smokers (any number of cigarettes), current smokers of less of 10 cigarettes/day, current smokers of more than 10 cigarettes/day., Results: Out of 200 patients 58 declared a history of cigarette smoking, 108 patients never smoked and the remaining 44 patients were cigarette smokers during cetuximab-based anticancer therapy. Of the 44 smokers, 18 smoked more than 10 cigarettes per day. No statistically significant differences in terms of response rate (RR) and time to progression (TTP) were identified between previous smokers and never smokers. RR in actual smokers was 13.6% and was lower than RR reported for non-smokers (27.1%; p = 0.023). In addition, the median TTP was 5.5 months in the non-smokers versus 2.8 months in the current smokers (p < 0.0001). A difference in terms of overall survival (OS) was detected between the two groups (p = 0.03). Comparing smokers of more than 10 cigarettes per day and smokers of less than 10 cigarettes per day no differences were detected in RR, TTP or OS., Conclusions: Our results suggest that cigarette smoking during anticancer treatment with a cetuximab-based regimen may be responsible for a decrease in RR and lead to a lower TTP.

Background: Although elderly patients (≥70 years) represent 30% of new diagnoses of soft tissue sarcoma (STS), they are underrepresented in clinical trials and are often unfit to receive standard anthracycline-based chemotherapy. Trabectedin is registered as a second-line treatment for advanced STS and is characterized by a favorable safety profile.Methods: The aim of this single-arm, phase 2 study was to investigate trabectedin (scheduled dose, 1.3-1.5 mg/m2 ) as a first-line treatment in elderly patients with advanced stage STS who are inoperable and are unfit to receive standard anthracycline-based chemotherapy. The coprimary endpoints were progression-free survival at 3 months (PFS3) and the rate of clinically limiting toxicities (CLTs). We also conducted an ancillary study on pharmacokinetics.Results: Twenty-four patients (12 men and 12 women) with a median age of 79 years (interquartile range [IQR], 74-83 years) were enrolled. The histological subtype was leiomyosarcoma in 46%, liposarcoma in 33%, and other histotypes in 21%. The median number of trabectedin courses was 4 (IQR, 3-6), with 7 patients (29%) receiving ≥6 cycles. Eight patients (33%) required dose reductions. The most frequent grade 3/4 adverse events were neutropenia in 9 patients (38%), fatigue in 5 patients (21%), and aminotransferase elevation in 5 patients (21%). PFS3, median PFS, and overall survival were 71% (80% CI, 57%-81%), 4 months, and 12 months, respectively. Ten patients (42% [80% CI, 28%-57%]) experienced CLTs. Trabectedin Cmax , half-life, clearance, and distribution volume were 1.28 ng/mL (standard deviation [SD], 0.58 ng/mL), 26.70 hours (SD, 9.09 hours), 39.98 L/h/m2 (SD, 14.08 L/h/m2 ), and 1460 L/m2 (SD, 561 L/m2 ), respectively.Conclusion: Trabectedin can be administered safely to elderly patients with STS who are unfit to receive anthracyclines. Pharmacokinetics in the elderly population was superimposable to historical data. [ABSTRACT FROM AUTHOR]

Abstract: Background: Scarce data are available about safety and efficacy of cetuximab in elderly metastatic colorectal cancer (mCRC) patients. Patients and methods: We retrospectively analysed 54 irinotecan-refractory mCRC patients aged≥70 years treated with cetuximab plus irinotecan and evaluated clinical outcome according to KRAS and BRAF mutational status. Results: Median age was 73 years (70–82). Main grade 3–4 toxicities were skin rash (15%), diarrhea (19%) and neutropenia (13%). Irinotecan dose reduction was necessary in 39% of patients. Fifty-two (96%) patients were analysed for KRAS and BRAF status. The 29 KRAS wild-type patients achieved better RR (31% vs 4%; p =0.030) and median PFS (4.21 months vs 3.95 months; p =0.034; HR: 0.50, 95% CI: 0.27–0.95) when compared with KRAS mutated ones. RR (41% vs 3%; p =0.001) and mPFS (4.57 months vs 3.78 months, p =0.001; HR: 0.35, 95% CI: 0.19–0.66) were significantly higher among the 22 KRAS and BRAF wild-type patients compared to the 30 KRAS or BRAF mutated ones. Conclusion: Cetuximab plus irinotecan has a favourable safety profile in elderly mCRC patients, but a reduced dose of irinotecan should be considered. Such a combination can be a useful option for elderly KRAS and BRAF wild-type patients. [Copyright &y& Elsevier]