Evidence-based appraisal of the upfront treatment for unresectable metastatic colorectal cancer patients

Colorectal cancer (CRC) is a significant health problem, with around 1 million new cases and 500000 deaths every year worldwide. Over the last two decades, the use of novel therapies and more complex treatment strategies have contributed to progressively increase the median survival of patients with unresectable advanced CRC up to approximately 30 mo. The availability of additional therapeutic options, however, has created new challenges and generated more complicated treatment algorithms. Moreover, several clinically important points are still in debate in first-line, such as the optimal treatment intensity, the most appropriate maintenance strategy, the preferred biologic to be used upfront in patients with KRAS wild-type CRC, and the need for more detailed information on tumor biology. In this moving landscape, this review analyses why the firstline treatment decision is crucial and how the choice may impact on further treatment lines. In addition, it focuses on results of major phase III randomized trial

Discordance in pathology report after central pathology review: Implications for breast cancer adjuvant treatment

Abstract Aim Pathological predictive factors are the most important markers when selecting early breast cancer adjuvant therapy. In randomized clinical trials the variability in pathology report after central pathology review is noteworthy. We evaluated the discordance rate (DR) and inter-rater agreement between local and central histopathological report and the clinical implication on treatment decision. Methods A retrospective analysis was conducted in a series of consecutive early breast cancer tumors diagnosed by local pathologists and subsequently reviewed at the Pathology Division of European Institute of Oncology. The inter-rater agreement (k) between local and central pathology was calculated for Ki-67, grading, hormone receptors (ER/PgR) and HER2/neu. The Bland–Altman plots were derived to determine discrepancies in Ki-67, ER and PgR. DR was calculated for ER/PgR and HER2. Results From 2007 to 2013, 187 pathology specimens from 10 Cancer Centers were reviewed. Substantial agreement was observed for ER (k0.612; 95% CI, 0538–0.686), PgR (k0.659; 95% CI, 0580–0.737), Ki-67 (k0.609; 95% CI, 0.534–0.684) and grading (k0.669; 95% CI, 0.569–0.769). Moderate agreement was found for HER2 (k0.546; 95% CI, 0444–0.649). DR was 9.5% (negativity to positivity) and 31.7% (positivity to negativity) for HER2 and 26.2% (negativity to positivity) and 12.5% (positivity to negativity) for ER/PgR. According to changes in Her2 and ER/PgR status, 23 (12.2%) and 33 (17.6%) systemic prescription were respectively modified. Conclusions In our retrospective analysis, central pathological review has a significant impact in the decision-making process in early breast cancer, as shown in clinical trials. Further studies are warranted to confirm these provocative results

Prediction of survival with second-line therapy in biliary tract cancer: Actualisation of the AGEO CT2BIL cohort and European multicentre validations

BACKGROUND: The benefit of second-line chemotherapy (L2) over standard first-line (L1) gemcitabine plus cisplatin (GEMCIS) or oxaliplatin (GEMOX) chemotherapy in advanced biliary tract cancer (aBTC) is unclear. Our aim was to identify and validate prognostic factors for overall survival (OS) with L2 in aBTC to guide clinical decisions in this setting. METHODS: We performed a retrospective analysis of four prospective patient cohorts: a development cohort (28 French centres) and three validation cohorts from Italy, UK and France. All consecutive patients with aBTC receiving L2 after GEMCIS/GEMOX L1 between 2003 and 2016 were included. The association of clinicobiological data with OS was investigated in univariate and multivariate Cox analyses. A simple score was derived from the multivariate model. RESULTS: The development cohort included 405 patients treated with L1 GEMOX (91%) or GEMCIS. Of them, 55.3% were men, and median age was 64.8 years. Prior surgical resection was observed in 26.7%, and 94.8% had metastatic disease. Performance status (PS) was 0, 1 and 2 in 17.8%, 52.4% and 29.7%, respectively. Among 22 clinical parameters, eight were associated with OS in univariate analysis. In multivariate analysis, four were independent prognostic factors (p < 0.05): PS, reason for L1 discontinuation, prior resection of primary tumour and peritoneal carcinomatosis. The model had the Harrell's concordance index of 0.655, a good calibration and was validated in the three external cohorts (N = 392). CONCLUSION: We validated previously reported predictive factors of OS with L2 and identified peritoneal carcinomatosis as a new pejorative factor in nearly 800 patients. Our model and score may be useful in daily practice and for future clinical trial design

Angiogenic inhibitors in gastric cancers and gastroesophageal junction carcinomas: A critical insight

Advanced gastric cancer ranks second as the global leading cause of cancer-related death and improvements in systemic chemotherapy have reached a plateau. Advanced molecular sequencing techniques help identifying patients more likely to respond to targeted agents; nevertheless we are still far from major breakthroughs. Although antiangiogenic drugs have produced notable advances, redundant pathways or mechanisms of resistance may limit their efficacy. Novel compounds have been recently developed to specifically target VEGF receptors, PlGF, FGF, MET, and angiopoietin. Ramucirumab, a monoclonal antibody specifically directed against the VEGFR-2, has emerged as a novel therapeutic opportunity. REGARD and RAINBOW were the first phase III studies to report the value of this strategy in gastric cancer patients, and other ongoing trials are testing novel antiangiogenic compounds. The aim of our review is to present the state-of-the-art of novel antiangiogenic compounds in advanced gastric cancer, underlying the biology, their mechanism of action, and their clinical results

Bevacizumab and first-line chemotherapy for older patients with advanced colorectal cancer: final results of a Community-based Observational Italian Study

BACKGROUND: Although the efficacy and safety of combining first-line chemotherapy with bevacizumab in elderly patients with colorectal cancer (CRC) is supported by the results of a phase III trial, real-practice data are limited. PATIENTS AND METHODS: Our multi-center, community-based observational study included 233 elderly patients with CRC (median age=73 years, range=70-84 years). Baseline comorbidities and geriatric evaluation were also analyzed. Pre-specified end-points of the study were safety, tolerability and outcome results. RESULTS: The incidence of both chemotherapy-induced and specific bevacizumab-related toxicities was low, and not influenced by baseline concurrent morbidities. Median progression free survival (PFS) and median overall survival (OS) were 9.9 months and 23.6 months, respectively. Fifty-six percent of patients received second-line chemotherapy. CONCLUSION: The upfront treatment of older patients with CRC with chemotherapy and bevacizumab is safe and efficacious in a real-world setting. No un expected toxicities were reported. Multi-dimensional geriatric evaluation is under-used in clinical practice

The PANDA study: a randomized phase II study of first-line FOLFOX plus panitumumab versus 5FU plus panitumumab in RAS and BRAF wild-type elderly metastatic colorectal cancer patients

Few data are available regarding the treatment of metastatic colorectal cancer elderly patients with anti-EGFR agents in combination with chemotherapy. FOLFOX plus panitumumab is a standard first-line option for RAS wild-type metastatic colorectal cancer. Slight adjustments in chemo-dosage are commonly applied in clinical practice to elderly patients, but those modified schedules have never been prospectively tested. Clinical definition of elderly (≥70 years old) patients that may deserve a more or less intensive combination therapy is still debated. Several geriatric screening tools have been developed to predict survival and risk of toxicity from treatment. Among those, the G8 screening tool has been tested in cancer patients showing the strongest prognostic value for overall survival, while the CRASH score can stratify patients according to an estimated risk of treatment-related toxicities