Reviews & Analysis

Hepatocellular carcinoma is a difficult-to-treat cancer and, after numerous phase III trials assessing kinase inhibitors have failed to meet their end points, sorafenib is the only accepted treatment for advanced stages of the disease. Now, the trial EVOLVE-1 has shown a lack of benefit for everolimus in the second-line treatment setting.

Cytotoxic agents are conventionally dosed on the basis of the maximum tolerated dose defined in phase I trials. A study assessing adverse events in over 2,000 patients treated with molecularly targeted agents suggests a need to redefine criteria for dosing of molecularly targeted agents, which should be based on randomized, dose-ranging phase II trials.

The treatment options available for hepatocellular carcinoma (HCC) vary depending on prognostic factors that include tumour characteristics and clinical status, particularly with regard to liver function. This Review discusses the links between disease phenotype, prognosis and therapy, focusing on the subclassification of patients with intermediate-stage HCC following the BCLC staging system, who are usually ineligible for curative resection and ablation treatments or liver transplantation; the therapies that are available for this patient subgroup are described.

The PREVAIL trial compared enzalutamide and placebo in patients with metastatic castration-resistant prostate cancer who had not received prior chemotherapy, demonstrating an improvement in overall survival and other clinical, radiographic, and biochemical outcomes. Herein, the implications of these data in the rapidly changing landscape of metastatic prostate cancer therapy are discussed.

The decision of patients with breast cancer to have contralateral mastectomies is often related to their genetic risk. However, the increasing frequency of this surgical approach is also associated with social and psychological issues such as celebrity experiences and fear of contralateral breast cancer. Appropriate counselling may better inform patients' surgical choices.

Active immunotherapy is emerging as an important addition to conventional cancer treatments, but many important questions remain. Optimal combinations of antigens, adjuvants and delivery vehicles need to be determined and effective strategies for overcoming tumour-associated immunosuppression ought to be developed. This Review provides an overview of new results from clinical studies of therapeutic cancer vaccines directed against tumour-associated antigens and discusses their implications for the use of active immunotherapy.

This Review explores breakthroughs in our understanding and treatment of acquired resistance to tyrosine kinase inhibitors in key molecular subtypes of non-small-cell lung cancer, which may be relevant across multiple different solid malignancies with oncogene-addicted subtypes. The potential of a number of clinical approaches to treat acquired resistance, from new drugs or drug combinations through to the use of more traditional therapies such as radiation or cytotoxic chemotherapy, are highlighted, and the implications for major changes in conducting clinical research in this setting are discussed.

Patients with oligometastases who develop a small number of metastatic lesions might achieve long-term survival with the use of ablative surgery or stereotactic radiotherapy. More patients are receiving aggressive treatment for oligometastatic disease, yet long-term survival might not be due to the treatments themselves, but rather to the selection of patients with slow-growing indolent disease. The authors examine the key evidence supporting or refuting the existence of an oligometastatic state and its appropriate treatment.

Gene mutations and genomic aberrations are the basis of tumour development. Over the past decade, single-gene mutations and genomic profiling have been increasingly used in multidisciplinary consultations for risk-assessment and treatment planning for patients with cancer. In this Perspective, the authors discuss the direct and indirect influences of genomic profiling on surgical decision making, and analyse the limitations and unresolved issues of a genotypic-approach to the surgical management of cancer.

Graft-versus-host disease (GVHD) is the most serious and challenging complication of allogeneic haematopoietic stem-cell transplantation (HSCT). There is a need for developing new approaches to mitigate GVHD and ultimately facilitate the use of allogeneic HSCT for the treatment of haematological cancers. In this Review, the authors discuss rationale, clinical evidence, and outcomes of the current GVHD prophylaxis and assess the clinical evidence for emerging approaches in the prevention of GVHD.

Healthy individuals carrying the t(14;18) translocation might never develop follicular lymphoma (FL). However, individuals with more than 1 in 10,000 cells carrying this translocation are at high-risk of developing FL. The identification of this high-risk population will help define the pathways driving FL and designing targeted therapies to use before its development.

The current drug development procedures are far from optimal, owing to the continuous development of the health systems and the clinical research landscape. The European Organisation for Research and Treatment of Cancer proposes in this Perspective the use of collaborative molecular screening platforms (CMSPs) as a new approach for drug development. These CMSPs have the advantage of optimizing expertise of several partners and combining efforts alongside with cost-sharing models for efficient patient selection.

The sinonasal cavities are affected by a range of tumour types, the most common of which are sinonasal squamous-cell carcinoma (SNSCC) and intestinal-type adenocarcinoma (ITAC). Compared with the main types of head and neck cancer, these sinonasal cancers have distinct epidemiological, clinical, aetiological, pathological and genetic characteristics, and require specialized treatment, bearing in mind their important anatomical location. All these aspects of ITAC and SNSCC are reviewed in this article.

Metronomic chemotherapy has undergone major advances as an antiangiogenic therapy. The discovery of the pro-immune properties of chemotherapy has established the intrinsic multitargeted nature of this therapeutic approach. André et al. describe the complex mechanisms of action of metronomic chemotherapy, and discuss the latest clinical data in both adult and paediatric populations, highlighting its potential role in the era of personalized medicine.

The recent results of the Early Breast Cancer Trialists' Cooperative Group meta-analysis have demonstrated that post-mastectomy radiotherapy reduces breast cancer recurrence and mortality in women with positive axillary lymph nodes—independently from the number of the lymph nodes involved—with no significant effect in patients with node-negative axillary status.

Around 20% of patients with colorectal cancer (CRC) have synchronous hepatic metastases at the time of presentation, highlighting the need for appropriate diagnostic and staging assessments. Furthermore, various approaches to the therapeutic management of such patients are available, and the treatment strategy used is influenced by clinical presentation. Herein, these aspects of the management of patients with CRC and synchronous liver metastases are comprehensively reviewed, focusing on the integration of surgical approaches within a multidisciplinary framework.

Over the past three decades, the interpretation of clinical trial outcomes in studies of advanced-stage non-small-cell lung cancer has changed. The robustness of findings from these trials has been called into question. We believe this change is a reflection of the improved understanding of molecular-based therapeutics and continued advances in this field.

The combination of conventional anatomical MRI and functional magnet resonance sequences–known as multiparametric MRI (mp-MRI) is emerging as an accurate tool for identifying clinically relevant tumours. This Review discusses the role of mp-MRI in the detection, staging, and treatment planning of prostate cancer.

MEK1 and MEK2 have key roles in tumorigenesis and, therefore, represent promising targets for cancer therapy; however, MEK1/2 inhibitors have been shown to have efficacy in only a narrow range of cancer types, mainly tumours that harbourBRAF or NRASmutations. In this article, the clinical experience with MEK inhibitors to date is reviewed, and potential approaches to overcoming therapeutic resistance and increasing the efficacy of treatment are discussed.

High-risk prostate cancer includes a heterogeneous group of patients with a range of prognoses, with some that can be fatal. The optimal management of this patient subgroup is evolving. We critically evaluate the existing literature focused on defining the high-risk population, the management of patients with high-risk prostate cancer, and future directions to optimize care.