News & Views

Dose-expansion cohorts (DECs) enable investigators to identify potentially effective drugs, for specific patient populations, in a single trial by assessing antitumour activity as early as possible. We discuss how the objectives, design and interpretation of DEC have evolved, and how DECs are changing the landscape of early drug development.

Treatment with pembrolizumab, an anti-PD-1 antibody, improved progression-free survival compared with investigator-choice chemotherapy in a phase II trial in patients with advanced-stage melanoma previously treated with ipilimumab. Two subsequent independent trials have confirmed that anti-PD-1 therapy is a better option than either chemotherapy or ipilimumab in the frontline setting.

Dairy cattle meat and milk factors are proposed as risks for colon and breast cancers. Several novel small circular DNAs that are genetically active in human cells have been isolated from bovine sera and milk. Such agents have also been detected in two lesions of multiple sclerosis. A unifying concept is presented putatively explaining the risks for these diseases that are associated with these factors.

Results of the UK Age trial suggest a significant benefit of annual mammography initiated at 39–41 years of age in preventing breast-cancer deaths occurring before the age of 50 years; however, this approach had no effect on the risk of breast-cancer death occurring before the age of 60 years and leads to prolonged deteriorations in quality of life owing to overdiagnosis.

A recent study has demonstrated that serial profiling of resistance mutations in cell-free DNA (cfDNA) collected from the blood of patients with colorectal cancer can be used to track tumour evolution throughout the therapeutic course. This approach has the potential to inform personalized medicine by enabling dynamic adaptation of therapy.

On the basis of an Early Breast Cancer Trialists' Collaborative Group meta-analysis, it has been suggested that the controversy over post-mastectomy radiotherapy (PMRT) for women with 1–3 involved lymph nodes should end. However, the meta-analysis lacks appropriate sample size, stratification, and uses outdated systemic regimens. Thus, the debate should continue.

Taxane-based regimens are among the preferred first-line chemotherapy options for metastatic breast cancer, with weekly paclitaxel considered equivalent to 3-weekly docetaxel. The CALGB 40502/NCCTG N063H (Alliance) trial has now compared bevacizumab plus weekly paclitaxel, nab-paclitaxel, or ixabepilone in this setting; ixabepilone was inferior and nab-paclitaxel was not superior, with a trend towards inferiority. Paclitaxel thus remains the standard-of-care taxane chemotherapy.

An analysis of reports from phase III trials (published between 2011 and 2013) investigating patients with solid tumours found widespread failings in both the conduct and reporting of subgroup analyses. Readers might well be misled by such analyses. Editors should, therefore, implement policies to reduce the risk of publishing misleading results.

Risk-reducing salpingo-oophorectomy (RRSO) is a standard intervention in BRCA1 or BRCA2 mutation carriers owing to its associated reduction in mortality related to ovarian and breast cancer. A study has now reported a beneficial impact of adjuvant RRSO in patients with BRCA1 mutations and breast cancer. However, various biases confound these results.

Pancreatic cancer remains a difficult-to-treat malignancy, yet nab-paclitaxel plus gemcitabine prolongs survival. Closer examination of the mechanism of action of nab-paclitaxel hints at a role for targeting KRAS. We discuss how nab-paclitaxel may be active in pancreatic cancer and how this informs the way forward to better treat patients with pancreatic cancer.

The efficacy of immunotherapy in metastatic melanoma is established, with anti-CTLA-4 and anti-PD-1 antibody-based therapies providing unexpectedly high responses and prolonged survival. The combination of nivolumab and ipilimumab is now poised to become the new standard of care, based on a 61% response rate in a recent randomized extended phase I/II trial, confirmed by phase III data presented at ASCO 2015.

The results of the ENESTg1 trial confirm the efficacy of imatinib, but not nilotinib, as a first-line treatment for gastrointestinal stromal tumours (GISTs) harbouring sensitizing mutations in KIT or PDGFRA. Nilotonib might prove to be beneficial in other subset of patients; however, there remains an urgent unmet need to address the GIST subtypes that are therapeutic orphans.

Despite the commercialization of HPV vaccines, cervical cancer remains a major cause of death, especially in developing countries. Recent data implicate a discrete population of cells within the cervical squamocolumnar junction in the pathogenesis of cervical precancerous lesions, indicating that ablation of these cells might reduce the rate of cervical cancer in high-risk populations.

In a recent international phase III trial, addition of bortezomib to a R-CHOP-like immunochemotherapy regimen for the first-line treatment of mantle-cell lymphoma resulted in a clinically meaningful extension of median progression-free survival. This finding emphasizes the role of targeted therapies in a relatively chemotherapy-refractory disease; however, therapeutic recommendations have to consider the observed haematotoxicity of this combination.

Randomized trial data support the use of laparoscopic surgery for colon cancer; however, such evidence was lacking for rectal cancer. Now, the COLOR II randomized trial gives minimally invasive resection of rectal cancer the 'green light', answering the question 'should laparoscopic surgery be used?' The new key question is 'who should be performing laparoscopic surgery for rectal cancer?'

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.

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.

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.