Reviews & Analysis

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.

Assessment of tumour burden has become an integral part of most oncology clinical trials, and enables the evaluation of the activity and efficacy of new cancer therapeutics in solid tumours. Although RECIST was developed to assess treatment activity in early phase II trials with tumour response as the primary end point, it is now applied across the spectrum from early phase I trials through to confirmatory phase III trials. Several questions regarding the role of RECIST in the rapidly changing landscape of oncology therapeutics, and the challenges faced in its evaluation, are highlighted.

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.

In 2016, the pace of biological insights into small-cell lung cancer (SCLC) was reflected in new treatment approaches that have suggested meaningful clinical benefit to patients. We focus on three highlights of 2016: preclinical studies defining NFIB as a putative driver of metastasis, and two clinical studies; one that assessed the efficacy of an agent targeting the Notch ligand DLL3, and the other that explored T-cell checkpoint-blockade therapies targeting PD-1 and CTLA-4.

In 2016, novel findings on the role of predisposing gene variants in sarcoma oncogenesis were published, as well as studies addressing novel molecular classifications and results from randomized controlled trials highlighting successful new treatments. Herein, we discuss these meaningful advances.

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.

In 2016, results of an extensive trial broadened the range of malignancies that can be treated with everolimus to include neuroendocrine tumours (NETs) of the lung and gastrointestinal tract. Furthermore, studies aimed at identifying biomarkers with increased specificity, and at better defining high-grade NETs have enabled substantial progress towards delivering effective targeted treatments to patients with NETs.

In the past year, clinical trials have provided important information on strategies to decrease treatment-associated toxicities in patients with head and neck cancer. In addition, the FDA approved the first immunotherapeutic agents for patients with recurrent and/or metastatic disease, based on the observation of durable responses to pembrolizumab in a phase Ib trial, and demonstration of improved survival and quality of life with the use of nivolumab versus chemotherapy in a phase III trial.

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.

The VOICE study addressed the oncologist–patient dyad by adding a two-sided intervention. The results of this ostensibly positive study are, at best, limited and, at worst, cosmetic because clinically relevant long-term outcomes were unaffected. VOICE is the first attempt at addressing complexity in this genre of studies and, even with its shortcomings, teaches us some important lessons.

Molecular cancer-classifier assays enable the diagnosis of a single cancer type for most patients with cancer of unknown primary (CUP), thus opening the door to the administration of site-specific therapies. Herein, I discuss how such therapies can improve the survival of patients with CUP, and the resulting paradigm shift towards tissue-of-origin diagnostics and treatments that is now becoming the standard of care for this patient population.

A multidisciplinary approach is essential for the optimization of patient care in oncology, especially in the current landscape, in which standard-of-care approaches to cancer treatment are evolving towards highly targeted treatments, precise image guidance and personalized cancer therapy. Herein, the authors discuss current career development pathways for oncologists, suggesting strategies to improve clinical training and research, with specific emphasis on the involvement of trainees in multidisciplinary teams.

Active surveillance has been proposed as a management option that reduces the risk of overtreatment in patients diagnosed with early stage prostate cancer. However, up until now, this approach has not been tested in a prospective, randomized fashion. The PROTECT study confirms that patients diagnosed with prostate cancer through prostate-specific antigen (PSA)-based screening are at a very low risk of cancer-related mortality, but patients undergoing active surveillance do have an increased risk of disease progression and metastases compared with those managed with upfront therapy.

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.

The UK Joint Committee on Vaccination and Immunization recently announced a further delay before considering the subject of widespread human papillomavirus (HPV) vaccination in teenage boys, thereby excluding an estimated 2.9 million boys from receiving an effective treatment in this interim period. Vaccination of boys can offer significant clinical, economic and ethical advantages.

Autophagy is fundamental to cellular homeostasis and also has a central role in the development and progression of cancer. However, autophagy is also required for optimal immune system function, including the development of an anticancer immune response. In this Perspective, the authors present the available preclinical and clinical evidence that autophagy might enhance the effectiveness of both immunogenic chemotherapy and radiotherapy, as opposed to the general view of inhibition of autophagy as an antitumour strategy.

Most patients with cancer who develop brain metastases have a very poor prognosis, especially those with brain metastases from non-small-cell lung cancer. The short life-expectancy of these patients, which is typically measured in weeks or a few months, raises an important question: do they benefit from whole-brain radiotherapy, or are they appropriately treated with best supportive care alone? A recent randomized trial sought to answer this question.

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.