News & Views

The success of cancer therapies is hampered by a paucity of suitable drug targets and the rapid development of therapy resistance. The concept of synthetic lethality provides a potential solution to these constraints via the identification of novel therapeutic vulnerabilities, as exemplified in two recent studies.

Data from the recent Stop 2G-TKI study confirm that around 60% of patients with chronic myeloid leukaemia who discontinue second-generation BCR–ABL1 tyrosine-kinase inhibitor (TKI) therapy after a sustained deep molecular response remain in remission for longer than 1 year. Importantly, the interim findings suggest that prior response to first-line TKI treatment might predict relapse risk after treatment discontinuation.

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.

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.

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.

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.

The SHIVA trial compared the efficacy of targeted agents selected on the basis of tumour molecular profiling (using an algorithmic approach) with that of physician's choice across multiple solid tumours; the trial was negative for the primary end point. We now discuss the challenges associated with precision medicine trial design and propose solutions learned from this trial.

Eaton et al. report a very strong association between institutional clinical trial accrual volume and the survival of patients with stage III NSCLC. The observed volume effect might have been exaggerated by artefact. More work is required to quantify the volume effect and understand its causes, before rushing to centralize care.

A theoretical radiobiological rationale supports the use of hypofractionated radiotherapy (higher radiation doses per fraction over a shorter period of time compared with conventional fractionation) for the treatment of prostate cancer. The investigators of two recently published phase III clinical trials with different designs have come to opposing conclusions regarding whether hypofractionated radiotherapy should be considered a new standard of care.

The use of programmed cell-death protein 1 (PD-1) inhibitors has become the standard-of-care approach for patients with advanced-stage, previously treated non-small-cell lung cancer. The inevitable adoption of these agents in the first-line setting is rapidly approaching, but the optimal strategy remains unclear. Two published clinical trial reports, examining different approaches, help to frame this question.

In three practice guidelines from ASCO, experts provide evidence-based recommendations that address overarching clinical questions for the management of patients with pancreatic cancer. These guidelines offer improved strategies for interdisciplinary patient management and highlight the need for further research in several areas.

In a recent study, the addition of olaratumab to doxorubicin chemotherapy for patients with soft-tissue sarcoma resulted in prolongation of progression-free survival by only 2.5 months, but an overall survival benefit of 11.8 months; the large disparity between these outcomes raises important questions. We discuss these results in relation to those of other trials, and the implications for sarcoma therapy.

In a paper published recently in Cell, Guarnerio et al. suggest that circular RNAs derived from cancer-associated chromosomal translocations have an oncogenic role; however, the experimental approach that the authors used was inadequate to generate sufficient evidence to prove this role, calling their study into question.

Annual thoracic CT screening is currently recommended for individuals deemed to be at high risk of developing lung cancer; however, Patz and co-workers now raise the very important question of choosing the optimal interval between screening exams, in order to balance the potential benefits and harms associated with each round of CT. Herein, we present important considerations for determining such intervals.

To improve the survival rates globally for paediatric patients with cancer, looking beyond level A evidence to treat children in low and middle-income countries is imperative. Herein, we discuss why metronomic chemotherapy, which is less toxic and more affordable, offers a pragmatic approach to provide new standards for patients with relapsed disease who have no alternatives.

We believe that current controversies surrounding screening might be better approached by shifting the question from 'does screening work?' to 'for whom does screening work?' We propose a 'rule-out/rule-in' principle as an intellectual basis and starting point for screening. Finally, we advocate the 'equal management of equal risks' principle as an unifying framework for developing simplified and consistent screening guidelines and practice.

The results of a number of studies have demonstrated the promise of adding intrahepatic arterial selective internal radiotherapy (SIRT) to chemotherapy for patients with liver metastases from colorectal cancer; however, the frequent progression of extrahepatic metastases observed in patients treated with SIRT in the SIRFLOX trial call the potential overall benefit of this approach into question.

The 21-gene recurrence score is a genetic assay developed to estimate the likelihood of distant recurrence in patients with oestrogen-receptor-positive, lymph-node-negative breast cancer treated with adjuvant endocrine therapy. Now, two studies explore how the 21-gene recurrence score has been used to inform treatment decisions in this setting and beyond.

Analysis of circulating tumour DNA (ctDNA) in blood samples provides a surrogate form of tumour biopsy (liquid biopsy) for determining EGFR and KRAS mutation status in patients with advanced-stage non-small-cell lung cancer. This approach obviates the need for a repeat biopsy, especially for the EGFR T790M mutation, which confers resistance to EGFR inhibition.