Despite recent advances in the management of colorectal cancer, metastatic disease remains challenging, and patients are rarely cured. However, a better understanding of the pathways implicated in ...the evolution and proliferation of cancer cells has led to the development of targeted therapies, that is, agents with action directed at these pathways/features. This approach is more specific to cells within which these pathways, such as epidermal growth factor receptor (EGFR), are overactive; this is in contrast to the relatively indiscriminate mechanism by which cytotoxic chemotherapy tends to affect rapidly dividing cells, regardless of their role. Although factors unique to a given patient, such as the location of the primary tumor (sidedness) or the presence of mutations that confer resistance, may limit the utility of these agents, targeted therapies are now a part of the treatment paradigm for metastatic colorectal cancer, and survival outcomes have significantly improved. This review provides an overview of the role of targeted therapy in the management of patients with colorectal cancer metastases as well as a discussion of issues in patient selection, with a focus on inhibitors of angiogenesis, EGFR‐targeted therapy, BRAF mutation–targeted therapies, and other novel strategies, including immunotherapy.
This review examines the current role of targeted therapies in metastatic colorectal cancer. It focuses on vascular endothelial growth factor– and epidermal growth factor receptor–targeted therapies as well as immunotherapy.
Among patients with hepatocellular carcinoma whose disease had progressed during receipt of sorafenib or other systemic therapy, median overall survival was 10.2 months with cabozantinib and 8.0 ...months with placebo. High-grade adverse events were as previously noted for the drug.
Hepatocellular carcinoma (HCC) is a leading cause of cancer‐related death worldwide, and the burden of this devastating cancer is expected to increase further in coming years. The collection and ...analysis of epidemiologic HCC data will play a critical role in guiding future disease prevention strategies and optimizing patient management. Previous epidemiologic studies have highlighted striking global variations in the incidence of HCC, which is particularly high in much of east Asia and sub‐Saharan Africa, and lower, but on the increase, in North America and most of Europe. This variation appears to be related to the complex etiology of HCC, with different risk factors, primarily infection with hepatitis B or hepatitis C virus, responsible for driving HCC incidence rates in different regions. Although previous studies have contributed considerably to the knowledge of HCC epidemiology, there are limitations associated with the currently available data, which arise from studies performed at different times in the past, using varying methodologies, and with diverse patient populations. A new and global approach to the study of HCC epidemiology is required if HCC disease prevention and treatment strategies are to be adequately directed and supported in coming years.
This article reviews key aspects of hepatocellular carcinoma and epidemiology, highlights the limitations of current data, and identifies the need for new approaches in future research.
Background
Methodological limitations of prior studies have prevented progress in the treatment of patients with borderline resectable pancreatic adenocarcinoma. Shortcomings have included an absence ...of staging and treatment standards and pre-existing biases with regard to the use of neoadjuvant therapy and the role of vascular resection at pancreatectomy.
Methods
In this manuscript, we review limitations of studies of borderline resectable PDAC reported to date, highlight important controversies related to this disease stage, emphasize the research infrastructure necessary for its future study, and present a recently-approved Intergroup pilot study (Alliance A021101) that will provide a foundation upon which subsequent well-designed clinical trials can be performed.
Results
We identified twenty-three studies published since 2001 which report outcomes of patients with tumors labeled as borderline resectable and who were treated with neoadjuvant therapy prior to planned pancreatectomy. These studies were heterogeneous in terms of the populations studied, the metrics used to characterize therapeutic response, and the indications used to select patients for surgery. Mechanisms used to standardize these and other issues that are incorporated into Alliance A021101 are reviewed.
Conclusions
Rigorous standards of clinical trial design incorporated into trials of other disease stages must be adopted in all future studies of borderline resectable pancreatic cancer. The Intergroup trial should serve as a paradigm for such investigations.
CALGB/SWOG 80405 was a randomized phase III trial that found no statistically significant difference in overall survival (OS) in patients with first-line metastatic colorectal cancer treated with ...chemotherapy plus either bevacizumab or cetuximab. Primary tumor DNA from 843 patients has been used to discover genetic markers of OS.
Gene mutations were determined by polymerase chain reaction. Microsatellite status was determined by genotyping of microsatellites. Tumor mutational burden (TMB) was determined by next-generation sequencing. Cox proportional hazard models were used, with adjusting factors. Interaction of molecular alterations with either the bevacizumab or the cetuximab arms was tested.
Patients with high TMB in their tumors had longer OS than did patients with low TMB (hazard ratio HR, 0.73 95% CI, 0.57 to 0.95;
= .02). In patients with microsatellite instability-high (MSI-H) tumors, longer OS was observed in the bevacizumab arm than in the cetuximab arm (HR, 0.13 95% CI, 0.06 to 0.30; interaction
< .001 for interaction between microsatellite status and the two arms). Patients with
mutant tumors had shorter OS than did patients with wild-type (WT) tumors (HR, 2.01 95% CI, 1.49 to 2.71;
< .001). Patients with extended
mutant tumors had shorter OS than did patients with WT tumors (HR, 1.52 95% CI, 1.26 to 1.84;
< .001). Patients with triple-negative tumors (WT for
/
/
) had a median OS of 35.9 months (95% CI, 33.0 to 38.8 months) versus 22.2 months (95% CI, 19.6 to 24.4 months ) in patients with at least one mutated gene in their tumors (
< .001).
In patients with metastatic colorectal cancer treated in first line, low TMB, and
and
mutations are negative prognostic factors. Patients with MSI-H tumors benefited more from bevacizumab than from cetuximab, and studies to confirm this effect of MSI-H are warranted.
PDF
