Safety and efficacy of nintedanib for the treatment of metastatic colorectal cancer.

INTRODUCTION: Nintedanib (BIBF 1200) is an oral tyrosine kinase inhibitor that targets the vascular endothelial growth factor (VEGFR), platelet-derived growth factor (PDGFR) and fibroblast growth factor (FGFR) receptors. It is approved in Europe in combination with docetaxel for patients with advanced lung adenocarcinoma who have progressed to first-line chemotherapy. However, its role in the treatment of metastatic colorectal cancer (mCRC) is uncertain. Recent results from the LUME-Colon 1 pivotal phase III trial showed only a marginal increase in progression free survival over placebo in refractory mCRC patients, with a toxicity profile similar to other antiangiogenic agents, and no benefit in overall survival. Areas covered: The aim of this review is to summarize the pharmacology, efficacy and safety profile of nintedanib in the context of mCRC, and to provide some perspective regarding the role of this drug in clinical practice. Expert commentary: Nintedanib provides limited clinical benefit in refractory CRC and its use in this clinical setting is not warranted. Efforts shall continue to pursue the identification of predictive biomarkers that allow the selection of subpopulations with a greater likelihood to benefit from this therapeutic approach, in order to improve the benefit-risk and cost-benefit ratios of this and other antiangiogenic agents.

Prognostic relevance of Src activation in stage II-III colon cancer.

Src belongs to a family of cytoplasmic tyrosine kinases that play a key role in tumor initiation and progression. Src activation has been associated with a more aggressive neoplastic phenotype and induces resistance to platinum agents in preclinical models. The aim of our study was to assess the prognostic and/or predictive value of Src activation in patients with stage II-III colon cancer. pSrc expression was assessed in paraffin-embedded tumor samples by immunohistochemistry (phospho-Y418, ab4816; Abcam). Cases were classified by staining intensity in 4 categories: no staining (0), weak (1+), moderate (2+), and intense (3+) staining. A total of 487 patients were evaluated (240 stage II, 247 stage III), of whom 298 (61%) had received adjuvant chemotherapy. Staining was absent in 78 (16%), weak in 262 (54%), moderate in 103 (21%), and intense in 44 (9%). High pSrc expression was significantly associated with decreased 5-year disease-free survival (39% versus 63% for patients with high versus low pSrc expression; hazard ratio, 0.56; P=.005) and overall survival (58% versus 74%; hazard ratio, 0.55; P=.02). Multivariate analysis confirmed pSrc expression as a significant prognostic factor both for disease-free survival and overall survival, independent of age, sex, tumor stage, bowel obstruction/perforation, or adjuvant chemotherapy. These findings illustrate the relevance of Src activation in colon cancer biology, conferring a poor prognosis to patients with early stage colon cancer regardless of adjuvant chemotherapy. Our findings may help improve prognostic stratification of patients for clinical decisions and open new avenues for potential pharmacologic manipulation that may eventually improve patients' outcomes.

Cost-Effectiveness Analysis of Different Sequences of the Use of Epidermal Growth Factor Receptor Inhibitors for Wild-Type KRAS Unresectable Metastatic Colorectal Cancer.

PURPOSE: Patients with unresectable wild-type KRAS metastatic colorectal cancer benefit from fluoropyrimidines (FP), oxaliplatin (O), irinotecan (I), bevacizumab (Bev), and epithelial growth factor receptor inhibitors (EGFRI). The most cost-effective regimen remains unclear. METHODS: A Markov model was constructed to examine the costs and outcomes of three treatment strategies: strategy A (reference strategy): EGFRI monotherapy in third line ([3L]; ie, first-line [1L]: Bev + FOLFIRI [FP + I] or FOLFOX [FP + O]; second line [2L]: FOLFIRI/FOLFOX; 3L: EGFRI); strategy B: EGFRI and I in 3L (ie, 1L: Bev + FOLFIRI/FOLFOX; 2L: FOLFIRI/FOLFOX; 3L: EGFRI + I); and strategy C: EGFRI in 1L (ie, 1L: EGFRI + FOLFIRI/FOLFOX; 2L: Bev + FOLFIRI/FOLFOX; 3L: best supportive care). Efficacy data of the treatments were obtained from the literature. Health system resource use information was derived from chart review and the literature. Using Euro-QOL 5 Dimensions, utilities were obtained by surveying medical oncologists and costs from the Ontario Ministry of Health and the literature. The perspective of the Canadian public health care system was used over a 5-year time horizon with a 5% discount in 2012 Canadian dollars. RESULTS: All three strategies had similar efficacy, but strategy C was most expensive. The incremental cost-effectiveness ratios (ICERs) for strategies B and C compared with A were 119,623 and 3,176,591, respectively. The model was primarily driven by the acquisition cost of the drugs. Strategy B was most cost effective when the willingness-to-pay threshold was > $130,000 per quality-adjusted life-year. Sensitivity analysis showed that strategy C would be cost-effective only when the progression-free survival of EGFRI is better than Bev in 1L with hazard ratio < 0.23 at willingness-to-pay of $150,000 per quality-adjusted life-year. CONCLUSION: First-line use of EGFRI in metastatic colorectal cancer is not cost effective at its current pricing relative to Bev.

Acquired ichthyosis as a paraneoplastic syndrome in Hodgkin's disease.

An 80-year-old man was admitted to hospital with low-grade fever, weight loss, asthenia and anorexia. Physical examination revealed generalised ichthyosis with palmoplantar hyperkeratosis. CT scan showed retroperitoneal and inguinal lymph node enlargement. An inguinal lymph node biopsy revealed Hodgkin's disease (nodular-sclerosing subtype). The patient received chemotherapy, showing a clear improvement of both skin lesions and lymph nodes.