Reviews & Analysis

Adolescent or young adult (AYA) patients with cancer are a unique group, with unique clinical needs; these patients are not entirely suited to cancer treatment and managment strategies designed either for paediatric patients, or older adult patients. In this Review, issues associated with the treatment, management and long-term outcomes of AYA patients with cancer are described in the context of acute lymphoblastic leukaemia and melanoma.

Hormone-receptor-positive breast cancer accounts for the majority of all breast cancers. The evolution of this disease from early stage to the metastatic setting leads to increased heterogeneity and the development of treatment resistance representing a great challenge for management decisions. In this Review, we examine the current evidence that can guide treatment decisions in patients with advanced-stage ER+ breast cancer, discuss how to tackle these therapeutic challenges and provide suggestions for the optimal management of this patient population.

Transarterial therapies in the setting of primary and secondary liver malignancies are an essential part of the oncology landscape. Most patients are not amenable to curative surgical intervention, which necessitates the use of alternative treatments that preserve quality of life whilst providing clinical benefit. The authors of this Review discuss intra-arterial techniques in light of the current levels of evidence to support their appropriate use in various clinical settings.

In patients with oesophageal cancer, the effect of lymphadenectomy on survival remains unclear. A recent retrospective cohort study suggests that extensive lymphadenectomy does not improve survival and might even hamper it in patients with early T-stage tumours. The available data show conflicting results and the introduction of neoadjuvant chemoradiotherapy might decrease any positive effect of extensive lymphadenectomy on survival.

Investigational metronomic chemotherapy involves frequent, regularly spaced, long-term administration of a sub-maximum tolerated dose. The phase III CAIRO3 trial evaluated continuous metronomic oral capecitabine, with bevacizumab, as a maintenance treatment in patients with metastatic colorectal cancer; a benefit in progression-free survival compared with observation only was observed, highlighting that metronomic chemotherapy could be a less toxic and convenient therapy.

The recognition of non-small-cell lung cancer (NSCLC) as a heterogeneous disease and ongoing efforts to characterize disease subtypes based on genotype and histology have resulted in dramatic improvements in outcomes for select patient subgroups. However, many challenges remain, not least acquired therapeutic resistance and the related issue of how to best use the available therapies. In this Review, the authors provide an overview of the key developments in NSCLC therapy, describe efforts to tackle therapeutic resistance, and discuss potential strategies to further optimize patient outcomes by stratifying treatments according to particular disease subtypes.

Predictive biomarkers are invaluable for successful and cost-effective treatment of cancer, however, biomarker discovery is difficult and requires multiple independent studies to identify suitable predictors of efficacy. Clinical trials performed in the USA, Europe or Asia can offer unique opportunities for biomarker discovery and validation. In this Perspectives, the authors describe the current fragmented approach to biomarker discovery and validation, highlighting how collaborative engagement of the academic, regulatory and pharmaceutical communities can help address these issues.

In the recent MAINSAIL trial, addition of lenalidomide to docetaxel for metastatic castration-resistant prostate cancer (mCRPC) was associated with inferior overall survival and more toxicity; thus, lenalidomide joins a long line of agents that failed to improve the efficacy of docetaxel. The process by which new therapies are advanced to phase III studies, particularly in combination with docetaxel, should be re-examined.

PET has evolved from a purely diagnostic imaging technique to a multifunctional modality that can provide diverse information of relevance to oncological management. This modality might offer the potential to improve patient care and outcomes by enabling better disease characterization, treatment-response monitoring, and follow-up assessment. Herein, the authors discuss the data supporting the use of PET in personalizing the clinical management of patients with locally advanced and metastatic non-small-cell lung cancer.

Traditionally, intertumour heterogeneity in breast cancer has been documented in terms of different histological subtypes, treatment sensitivity profiles, and clinical outcomes among different patients. High-throughput molecular profiling studies have confirmed that spatial and temporal intratumour heterogeneity of breast cancers exist at a level beyond common expectations. In this Review, the authors describe the different levels of tumour heterogeneity, and discuss the strategies that can be adopted by clinicians to tackle treatment response and resistance issues associated with such heterogeneity for the optimal clinical management of breast malignancies.

Currently, most novel chemotherapies are initially tested in tumour cell lines and xenografts, which generally fail to reflect the full spectrum of tumour-specific mutations, and might explain the low success rates of experimental treatments. In this Perspectives, the mouse hospital co-clinical trial project is described, which enables treatments to be tested in mouse models that accurately reflect the tumour characteristics of individual patients.

When a pregnant woman is diagnosed with cancer, clinical management is complicated by concerns about the possible detrimental effects of cancer treatments on pregnancy outcome and the health of the baby. Evidence about the outcomes of children after maternal chemotherapy for cancer during pregnancy is growing and we can say 'the kids are all right'.

The widespread use of PSA screening and transrectal ultrasound (TRUS)-guided prostate biopsy has resulted in an epidemic of overdetection and overtreatment of prostate cancer. The use of targeted magnetic resonance (MR) and ultrasound fusion guided prostate biopsy promises to improve the detection rate of high-risk prostate cancer—reducing the issue of overdetection and overtreatment.

A lack of clinical investigation, which has arguably become more pronounced in the past decade, currently hinders progress in cancer surgery research, and ultimately the treatment of patients with cancer. This Perspectives describes the major barriers to progress in surgical oncology, and how improvements might be made in this important, but often overlooked, aspect of cancer treatment.

Owing to the institution of annual low-dose CT for lung cancer screening in the USA, the presumed increase in detection of early stage lung cancers elicits many questions about so-called 'grey areas' of the management of this disease that have been inadequately addressed to date. Herein, important and potentially difficult ambiguous cases that oncologists might come across are discussed.

Cancer stem cell (CSC) populations are increasingly recognized in most malignancies and are hypothesized to contribute to cancer proliferation, relapse, and metastasis. Thus, the highly conserved stem-cell signal transduction pathways involved in development and tissue homeostasis that are frequently active in CSCs represent prime targets for targeted therapies against this characteristically treatment-resistant and highly tumorigenic cell population. This Review provides a update on the clinical development of therapies targeting Wnt, Notch, and Hedgehog, three prominent stem-cell signalling pathways that are upregulated in CSCs.

Although neoadjuvant chemotherapy (NACT) does not prolong survival compared with adjuvant chemotherapy, this approach does not increase the risk of locoregional recurrence, and the high rates of response following NACT have had a considerable impact on locoregional treatment considerations. In particular, NACT can decrease the need for mastectomy and axillary lymph-node dissection. This Review discusses issues relating to the identification of ideal candidates for NACT, and also those surrounding surgery of the breast and axilla in women with breast cancer who receive NACT.

The survival rates of patients with pancreatic cancer are low and have not improved significantly over the past three or four decades. Thus, effective treatments for this disease are an urgent unmet need. Novel treatment paradigms will probably be required, and many new therapeutic approaches are being tested in this setting. This Review outlines the state-of-the-art therapies for patients with pancreatic cancer, as well as the novel treatment strategies that are the focus of drug-development efforts.

Recent data indicate that immune-checkpoint inhibitors have activity in patients with chemotherapy-refractory metastatic urothelial bladder cancer and further confirmatory trials are ongoing. Future research, including development of informative biomarker assessments, investigation of combination therapy and testing agents at earlier stages of disease is required to further explore this potential benefit.

Several guidelines propose the use of Ki67 expression to select which patients with early stage breast cancer and 1–3 positive nodes should not receive adjuvant chemotherapy. In this Perspective, the authors discuss why, in 2015, the oncologist should not rely on the use of this biomarker for decision-making in this patient population—owing to lack of analytical validity of Ki67 staining, its poor performance for prognostic purposes, and no strong evidence indicating that Ki67 staining predicts the efficacy of adjuvant chemotherapy.