Reviews & Analysis

Demonstration of the clinically significant activity of bevacizumab in advanced-stage ovarian cancer has attracted a great deal of interest. Here, we summarize the two positive phase III trials that led to EMA approval of bevacizumab as first-line therapy and discuss the optimum use of the drug in this disease.boxed-text

Is there a precise end point that could enable us to compare neoadjuvant and adjuvant endocrine therapy outcomes? A reliable short-term surrogate to assess the potential of endocrine drugs in the adjuvant setting? In this Review, Goncalves et al. summarize the studies in which the proliferation marker Ki 67, measured during neoadjuvant treatment, has predicted accurately and consistently the results of much larger studies in the adjuvant setting.

The current system for the development of anticancer drugs is not fit for purpose. In this Review article, this system is examined from the perspective of the drug company, offering a fresh look at development from target identification up to registration.

Despite advances in treating multiple myeloma with the proteasome inhibitor bortezomib and the immunomodulatory drugs thalidomide and lenalidomide, most patients eventually relapse. In this Review, the authors discuss how next-generation inhibitors and immunotherapy agents have been developed based on an improved understanding of the biology of the disease, and highlight the challenges associated with these therapeutic approaches.

In terms of drug development, the main driving force should be optimized benefit–risk to patients; however, no drug can be of real benefit unless it has achieved approval from the regulatory agencies. This Perspectives allows us a peek behind the door of one of those agencies (EMA) and outlines the hurdles that exist and that need to be overcome before we can have an efficient, biomarker-driven drug development program. Points for discussion in the community are raised and suggestions are put forward.

The BOLERO-2 and CLEOPATRA trials evaluated everolimus for estrogen receptor-positive and pertuzumab for HER2-positive metastatic breast cancer. Both agents enhanced the efficacy of standard therapy, were relatively well tolerated and should be approved for therapeutic use. These data confirm that targeting both major driver and escape pathways improves treatment outcomes.

Clinical trials have consistently demonstrated the superior sensitivity of human papillomavirus (HPV) testing compared with cytology (Pap) testing for identifying women at risk of cervical cancer. Rijkaart et al. have now shown that adding HPV testing to routine cervical cancer screening can further reduce the risk of cervical cancer compared to Pap testing alone.

DNA repair as a therapeutic target has received considerable attention in the treatment of non-small-cell lung cancer (NSCLC). In this Review, Postel-Vinay et al. discuss how optimizing treatment of NSCLC according to DNA-repair biomarkers, such as ERCC1, BRCA1 or RRM1, may aid clinical decision making and improve the outcome of patients with NSCLC.

Should dynamic contrast-enhanced (DCE)-MRI be used in the assessment of drug-development of antivascular agents? In this Review, O'connor et al. discuss whether data from DCE-MRI are reliable and reproducible biomarkers of drug efficacy, and whether they assist in dose selection and drug scheduling in the design of early clinical trials.

Antiangiogenic therapies have secured a role in the treatment of multiple cancers. However, the success of this targeted therapy is not as great as originally anticipated. In this Perspectives article, the authors use data from clinical trials to uncover where some of the problems with this therapy lie, discuss exciting recently published data and look to what the next steps should be.

Late toxicities from radiation therapy are frequent in patients with Hodgkin lymphoma and can hamper survival. These late toxicities should decrease with modern radiation therapy but results are not mature and so the importance of this decrease is still unknown. Hence, all studies in Hodgkin lymphoma must report long-term outcome.

The increasing reliance on hazard ratios for the assessment of clinical trial data prompted this Perspectives article, designed to outline the uses and misuses of this popular statistical value. The authors use real trial data and synthetic examples to explain how the hazard ratio is derived and why the numerical value of a survival measure should also be published alongside it.

Patients with cancer who also have hepatitis B virus (HBV) or hepatitis C virus (HCV) infection have a significant morbidity and mortality. HBV reactivation is a serious but preventable complication of immunosuppressive therapy. The authors discuss the epidemiology, pathogenesis, risk factors, and clinical and laboratory manifestations associated with the reactivation of HBV and HCV during immunosuppressive therapy, and discuss strategies for the prevention and treatment of viral reactivation.

Melanoma has emerged as the paradigm tumor for drug development through mutation-targeted therapies (inhibitors targeting BRAF, MEK, and c-KIT) and immunotherapy. Exploring the combinations of both approaches is a challenge that will require scientific rationale and the cooperation of the pharmaceutical industry. But, with these challenges comes another opportunity to change the paradigms in drug development.

Options to treat late-stage castration-resistant prostate cancer continued to increase in 2011, as three agents with different mechanisms of action prolonged life and a fourth reduced the morbidity of skeletal metastases. These outcomes contrasted with the heightened controversy generated by the recommendation against PSA screening and other early detection strategies.

2011 saw improvements in our understanding of B-cell malignancies: insights into the genomic basis of chronic lymphocytic leukemia were achieved; reduced treatment intensity caused fewer toxic effects in early-stage Hodgkin lymphoma; first-line rituximab maintenance therapy improved outcome in follicular lymphoma; and selected patients with diffuse large-cell lymphoma benefited from the addition of bortezomib.

Randomized controlled trials (RCTs) pose dilemmas in terms of the tension between the therapeutic obligations of the physician and the scientific obligations of the investigator. Clinical equipoise is often regarded as a solution to this problem. The authors critically evaluate clinical equipoise and highlight its flaws as an ethical requirement for RCTs and propose an alternative method of risk–benefit assessment.

Recent phase III trials of denosumab, a monoclonal antibody that inhibits RANKL, have demonstrated superiority over zoledronic acid in reducing skeletal morbidity in patients with metastatic bone disease. Brown and Coleman describe the emerging role of denosumab in maintaining bone health in the oncology setting and discuss the factors to consider when deciding whether to use bisphosphonates or denosumab in clinical practice.