Review Articles in 2016

The treatment landscape for lymphoma has become crowded, requiring efficient prioritization for expedited drug development. New challenges include the optimal duration of therapy, as well as the need to balance cost, benefit, and late-onset toxicity. Herein, the authors overview of the most-promising agents in clinical development for the treatment of lymphoma, and provide expert opinion on new strategies to streamline drug development as well as approaches for patient selection and for incorporating new end points into clinical trials.

In 2016, a revised WHO classification of glioma was published, in which molecular data and traditional histological information are incorporated into integrated diagnoses. Herein, the authors highlight the developments in our understanding of the molecular genetics of gliomas that underlie this classification, and review the current landscape of molecular biomarkers used in the classification of disease subtypes. In addition, they discuss how these advances can promote the development of novel pathogenesis-based therapeutic approaches, paving the way to precision medicine.

After curative treatment, 30% of patients with stage I–III and up to 65% of patients with stage IV colorectal cancer (CRC) develop recurrent disease. Thus, surveillance for disease recurrence is clearly needed in these patients, but controversy surrounds the optimal follow-up approaches. Herein, the current evidence relating to surveillance strategies for patients with CRC is comprehensively reviewed, and the future development of patient-centred programmes is discussed.

The PARP inhibitor olaparib has been approved for clinical use in patients with ovarian cancer withBRCA 1/2 mutations; however, this agent, which can confer substantial improvements in patient survival might also be effective in those without a BRCA mutation. Here, the authors describe the potential for expanding the use of BRCA-mutation testing and PARP inhibition beyond those who are likely to have a BRCAmutation.

Recent advances in molecular biology and our understanding of the development of colorectal cancer (CRC) has enabled the more-precise use of innovative targeted therapies for this disease. In particular, large databases to capture and store genomic information on causative genes frequently deregulated in CRC, the use of gene-expression profiling to differentiate the subtypes of CRC into prognostic and predictive groups, and results from next-generation sequencing analyses have led to an appreciation of the extensive intratumour heterogeneity of this disease. The authors highlight these advances, place them into clinical context, and present other novel targets and therapeutic opportunities on the horizon.

Emerging evidence suggests that the prolonged therapeutic use of androgen receptor (AR)-targeting agents in patients with prostate cancer induces histological dedifferentiation and lineage alterations. Roubaud and colleagues propose that AR suppression creates a checkpoint by which potent therapies exert a selective pressure on prostate cancer cells, favouring dedifferentiated and/or treatment-resistant cell lineages. The authors present a new clinical trial strategy in which rapid drug cycling is used to delay the onset of resistance and treatment-induced lineage crisis in patients with prostate cancer.

In this Review, the authors describe the developing therapeutic landscape for patients with muscle-invasive bladder cancer. In particular, the data supporting the use of neoadjuvant cisplatin-based chemotherapy as a standard of care, the potential impact of genomic profiling on treatment approaches, and the emerging importance of immunotherapy are discussed.

Immune-checkpoint inhibitors are revolutionizing the treatment of many types of solid cancer. Expression of the inhibitory immune-checkpoint proteins programmed cell-death 1 (PD-1) and its ligands (PD-L1 and PD-L2) are frequently detected in haematological malignancies, and agents targeting these proteins have activity in such diseases, notably Hodgkin lymphoma. Herein, the current evidence supporting the roles of PD-1–PD-L1 blockade in the treatment of various B-cell malignancies is reviewed.

Tyrosine kinase inhibitors (TKIs) are the most common agents used for the treatment of patients with chronic myeloid leukaemia (CML). Several agents are available for frontline treatment, or after the development of resistance or intolerance to agents previously used. Herein, the authors evaluate differences between available TKIs, and discuss several end points that can be considered when selecting the first and subsequent lines of treatment of patients with CML.

Patients diagnosed with cancer through an emergency presentation have worse outcomes compared with those in whom cancer is diagnosed through other routes; therefore, reducing the number of patients presenting as an emergency with cancer will improve patients' outcomes. In this Review, the authors describe the available evidence in this area, and provide recommendations for future research, clinical practice and public health policy.

To form metastases, cancer cells must leave the immunosuppressive tumour microenvironment and traffic, predominantly in the circulation, to new tissue sites, where they must then expand. During this process, the tumour cells are open to attack by the immune system. This Review highlights the possible mechanisms used by circulating tumour cells in the blood and disseminated tumour cells in other tissues to evade, escape, or subvert the immune system in order to survive and form metastatic lesions.

Distant metastasis remains a common cause of death in patients with solid tumours, even after treatment with surgery, radiotherapy and/or chemotherapy. Treatment itself can sometimes cause or promote metastasis by increasing the number of circulating tumour cells. The authors of this article discuss preclinical and clinical data concerning cancer treatments, circulating tumour cell mobilization and other factors that might promote metastasis.

Intrinsic pathophysiological barriers limit the delivery of drugs to pancreatic cancers, contributing to the limited effectiveness of treatment. Nanomedicine approaches have the potential to overcome many of these drug-delivery challenges, and two nanoparticle therapies are now approved for the treatment of this disease. The authors discuss the key pathobiological barriers that must be overcome, the approaches to nanomedicine that have been pursued to date, and those that are the focus of ongoing research.

In the past 5 years, results from large-scale whole-exome sequencing studies have brought new insight into the clonal heterogeneity and evolution of multiple myeloma, a genetically complex disease. Herein, the authors describe the driver gene alterations and sequential acquisition of the main genomic aberrations involved in this disease, with a focus on the clonal heterogeneity of multiple myeloma and its clinical implications.

The prevalence rates of obesity, type 2 diabetes mellitus, and cancer are increasing globally. Herein, the relationships between these diseases and their treatments are reviewed, and the practical principles relevant to the increasingly common challenge of managing patients who have been diagnosed with both diabetes and cancer are outlined.

Expediting the diagnosis of cancer is generally considered to result in improved patient outcomes, and much effort is applied to achieving this goal. Herein, the authors describe the various aspects of early diagnosis of cancer including the potential benefits, methods, most suitable patients and likely costs, in the context of the UK National Health Service.

Many of the molecular pathways that are aberrant in brain tumours result in reprogramming of metabolism, which creates opportunities forin vivometabolic imaging to improve diagnosis, patient stratification, and disease monitoring. Herein, the molecular basis and strategies for non-invasive metabolic imaging of brain tumours are reviewed.

Contrary to other cancer types, histopathology remains the mainstay of diagnosis and classification of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). Increasing knowledge of the molecular genetics and biology of GEP-NENs promises to improve classification of disease subtypes, and thus the management of the disease. Herein, the authors discuss the features of GEP-NENs that, as prognostic or predictive biomarkers, could form the basis for a novel, clinically useful molecular classification system.

The advent of next-generation sequencing technologies has substantially improved our understanding of prostate cancer genetics; however, this knowledge is currently not fully reflected in the form of targeted treatment strategies. In this Review, the authors summarize our current understanding of the genetic landscape of prostate cancer and the challenges to treatment posed by the presence of considerable intratumour and intertumour heterogeneity.

Metronomic chemotherapy regimens were developed to optimize the antitumour efficacy of antiangiogenic agents and to reduce toxicity of antineoplastic drugs, but the effectiveness of this approach also relies on other mechanisms, such as the stimulation of the immune system. Investigating the pharmacokinetic and pharmacodynamic properties of agents administered in metronomic regimens will enable a more-personalized therapeutic approach. Herein, Bocci and Kerbel discuss results from early phase and pilot clinical studies that support the important link between pharmacokinetics and metronomic chemotherapy.