NeuroPredict: study of the predictive value of ABCB1 genetic polymorphisms and associated clinical factors in chronic chemotherapy-induced peripheral neuropathy (CIPN).

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common entity (30%-40%) and can significantly limit the quality of life of patients, especially those that persist for more than 6 months after treatment (chronic neuropathy). Studies have shown a possible association between the presence of genetic polymorphisms in ABCB1 and the development of acute CIPN, although this relationship with chronic CIPN remains unexplored. This is an analytical observational case-control study defined by the presence (cases) or absence (controls) of CIPN at 6 months after the end of the neurotoxic drug. Our aim is to demonstrate whether these ABCB1 polymorphisms also influence the chronification of this toxicity, as well as the clinical factors that can help us to predict it. Methods: The study included 152 patients treated with tri-weekly oxaliplatin (O) or weekly paclitaxel (P); 86 cases and 66 controls. Clinical and analytical parameters were analysed including the study of ABCB1 genetic polymorphisms in a blood sample. Results: ABCB1 genetic polymorphisms C1236T (rs1128503) and C3435T (rs1045642) are associated with the development of chronic CIPN in patients treated with P. No differences were found in patients treated with O. Other predictive factors to be considered in the development of this toxicity are age >60 years, BMI ≥30, toxic habits and cardiovascular risk factors. Conclusion: CIPN is a common and understudied toxicity, despite being a limiting factor in the quality of life of many patients. As described in acute CIPN, our study demonstrates the relationship between chronic neuropathy and being a carrier of specific polymorphisms (C1236T and C3435T) of the ABCB1 gene in patients treated with P. In addition, there are modifiable factors (obesity, smoking, or alcohol) that may influence its development. Further prospective studies are needed to investigate genetic and clinical modifiable factors predisposing to CIPPN to develop prevention and treatment strategies.

Gemcitabine-erlotinib versus gemcitabine-erlotinib-capecitabine in the first-line treatment of patients with metastatic pancreatic cancer: Efficacy and safety results of a phase IIb randomised study from the Spanish TTD Collaborative Group.

BACKGROUND: Gemcitabine and erlotinib have shown a survival benefit in the first-line setting in metastatic pancreatic cancer (mPC). The aim of this study was to assess whether combining capecitabine (C) with gemcitabine + erlotinib (GE) was safe and effective versus GE in patients with mPC. PATIENTS AND METHODS: Previously untreated mPC patients were randomised to receive G (1000 mg/m2, days 1, 8, 15) + E (100 mg/day, days 1-28) + C (1660 mg/m2, days 1-21) or GE, q4 weeks, until progression or unacceptable toxicity. Primary end-point: progression-free survival (PFS); secondary end-points: overall survival (OS), response rate, relationship of rash with PFS/OS and safety. RESULTS: 120 patients were randomised, median age 63 years, ECOG status 0/1/2 33%/58%/8%; median follow-up 16.5 months. Median PFS in the gemcitabine-erlotinib-capecitabine (GEC) and GE arms was 4.3 and 3.8 months, respectively (hazard ratio [HR]: 0.88, 95% confidence interval [CI]: 0.58-1.31; p = 0.52). Median OS in the GEC and GE arms was 6.8 and 7.7 months, respectively (HR: 1.09, 95% CI: 0.72-1.63; p = 0.69). Grade 3/4 neutropenia (GEC 43% versus GE 15%; p = 0.0008) and mucositis (GEC 9% versus GE 0%; p = 0.03) were the only statistically significant differences in grade 3/4 adverse events. PFS and OS were significantly longer in patients with rash (grade ≥1) versus no rash (grade = 0): PFS 5.5 versus 2.0 months (HR = 0.39, 95% CI: 0.26-0.6; p < 0.0001) and OS: 9.5 versus 4.0 months (HR = 0.51, 95% CI: 0.33-0.77; p = 0.0014). CONCLUSION: PFS with GEC was not significantly different to that with GE in patients with mPC. Skin rash strongly predicted erlotinib efficacy. The study was registered with ClinicalTrials.gov: NCT01303029.

Bevacizumab in advanced breast cancer: a new model for the assessment of activity in non-first-line treatment regimens.

The activity of bevacizumab (BVZ) in advanced lines is not well known. In the treatment of metastatic breast cancer, the response rate and time to treatment failure (TTF) decrease with progression through successive therapeutic lines. The objective of this study was to compare BVZ activity in advanced treatment lines with that achieved in the previous line in routine clinical practice. Ninety-six patients who had received BVZ treatment in second or subsequent treatment lines were selected from five Spanish hospitals. Analysis was carried out of the differences in TTF and response rate in the lines with BVZ and those in earlier lines. Data analysis was carried out in two different ways: (a) by comparing treatment groups according to the treatment line received, using a Cox regression model with random effects, and the McNemar test to analysis the response rate, and (b) by comparing intrapatient data, using the Wilcoxon signed-rank test. In 62 patients, the TTF (adjusted for treatment line) was longer in the BVZ treatment line than that in the previous line. In the BVZ lines, there was a significant reduction in the probability of treatment failure [hazard ratio 0.52; 95% confidence interval (CI) 0.38-0.71]. The median TTF was 4.27 months (95% CI 3.7-5) in the previous line and 6.18 months (95% CI 5.5-7.93) in the BVZ line. The percentage of patients with an objective response was 33.3% in the previous lines and 52.1% (P=0.005) in the BVZ line. Contrary to expectation, more patients showed better results with the BVZ line than with the previous line. BVZ treatment in advanced lines improves the results obtained in previous treatment lines. This suggests that BVZ is active in advanced lines and that it produces favourable changes in the natural history of patients with metastatic breast carcinoma.